Mechanistic description
Mechanistic Overview
Senescence-Associated Myelin Lipid Remodeling starts from the claim that modulating PLA2G6/PLA2G4A within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "## Molecular Mechanism and Rationale The senescence-associated myelin lipid remodeling hypothesis centers on the aberrant activation of phospholipase A2 (PLA2) enzymes, specifically PLA2G6 and PLA2G4A, within p21+ senescent oligodendrocytes. Under physiological conditions, myelin membranes maintain their structural integrity through a precise lipid composition rich in galactosylceramide, sulfatide, and phosphatidylcholine, which creates the optimal dielectric properties necessary for saltatory conduction. However, in senescent oligodendrocytes, the cyclin-dependent kinase inhibitor p21 triggers a cascade of metabolic reprogramming that fundamentally alters lipid homeostasis. The molecular pathway begins with p21-mediated cell cycle arrest, which paradoxically leads to increased metabolic activity and oxidative stress. This cellular stress activates the calcium-dependent cytosolic phospholipase A2α (PLA2G4A) through phosphorylation by mitogen-activated protein kinases (MAPKs), particularly p38 and ERK1/2. Simultaneously, the calcium-independent phospholipase A2β (PLA2G6) becomes upregulated through NF-κB-mediated transcriptional activation, a hallmark of the senescence-associated secretory phenotype (SASP). Both enzymes cleave the sn-2 position of glycerophospholipids, liberating arachidonic acid and lysophospholipids from myelin membranes. The resulting increase in membrane fluidity occurs through multiple mechanisms. Arachidonic acid incorporation into membrane phospholipids creates kinks in the fatty acid chains due to its polyunsaturated nature, disrupting the tight packing of lipid molecules. Lysophospholipids, particularly lysophosphatidylcholine and lysophosphatidylserine, act as membrane detergents, further destabilizing the lipid bilayer structure. This compositional shift reduces the electrical resistance of myelin from approximately 10^9 Ω·cm to 10^7 Ω·cm, while simultaneously increasing membrane capacitance. The altered biophysical properties impair action potential propagation by creating current leakage points and reducing conduction velocity, making axons energetically vulnerable and prone to degeneration through calcium influx and mitochondrial dysfunction. ## Preclinical Evidence Extensive preclinical validation has emerged from multiple model systems demonstrating the relationship between PLA2 dysregulation and myelin dysfunction. In 5xFAD mice, a well-established Alzheimer’s disease model, immunohistochemical analysis reveals a 3.5-fold increase in PLA2G4A expression within corpus callosum oligodendrocytes by 12 months of age, coinciding with a 40-60% reduction in myelin basic protein (MBP) immunoreactivity. Mass spectrometry analysis of isolated myelin fractions shows a 25% decrease in galactosylceramide content and a corresponding 180% increase in lysophosphatidylcholine levels compared to age-matched wild-type controls. Electrophysiological studies in aged C57BL/6J mice (24 months) demonstrate compound action potential conduction velocities reduced by 35% in corpus callosum preparations, correlating with electron microscopy findings of myelin vacuolation and decreased g-ratio (axon diameter/fiber diameter) from 0.77 to 0.84. Lipidomics analysis reveals elevated arachidonic acid metabolites, including prostaglandin E2 and leukotriene B4, indicating active inflammatory lipid cascades downstream of PLA2 activation. In vitro studies using primary oligodendrocyte cultures treated with hydrogen peroxide to induce senescence show robust upregulation of both PLA2G6 and PLA2G4A within 48 hours, accompanied by β-galactosidase positivity and p21 expression. Fluorescence recovery after photobleaching (FRAP) experiments demonstrate increased membrane fluidity in myelin-like membranes produced by senescent oligodendrocytes, with diffusion coefficients increasing from 2.1 × 10^-9 cm²/s to 4.7 × 10^-9 cm²/s. Patch-clamp recordings from co-cultured neurons show reduced action potential amplitude and increased refractory periods when interfaced with senescent oligodendrocyte-derived myelin. Caenorhabditis elegans studies using neuronal-specific PLA2 overexpression models recapitulate key phenotypes, including reduced locomotion velocity and increased susceptibility to oxidative stress, validating the evolutionary conservation of this mechanism across species. ## Therapeutic Strategy and Delivery The therapeutic approach encompasses both pharmacological PLA2 inhibition and nutritional lipid supplementation strategies. The primary drug modality involves selective small molecule inhibitors targeting PLA2G4A and PLA2G6 enzymes. Efipladib (formerly known as WAY-196025), a potent PLA2G4A inhibitor with an IC50 of 0.9 μM, demonstrates excellent brain penetration with a brain-to-plasma ratio of 0.6 following oral administration. The compound exhibits favorable pharmacokinetics with a half-life of 8-12 hours in humans, allowing for twice-daily dosing at 200-400 mg. For PLA2G6-specific targeting, ML355 represents a selective inhibitor with minimal off-target effects, showing 100-fold selectivity over PLA2G4A. Its lipophilic properties (LogP = 3.2) facilitate blood-brain barrier penetration, though its shorter half-life of 4 hours necessitates modified-release formulations or prodrug approaches. Nanoparticle delivery systems utilizing lipid nanoparticles (LNPs) or polymeric PLGA microspheres could provide sustained CNS exposure while minimizing systemic toxicity. Complementary lipid supplementation therapy involves oral administration of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) at doses of 2-4 grams daily, along with phosphatidylserine (300-600 mg daily) and sphingomyelin (200-400 mg daily). These supplements aim to restore optimal myelin lipid composition and counteract the inflammatory mediators produced by aberrant PLA2 activity. Gene therapy approaches utilizing adeno-associated virus (AAV) vectors targeting oligodendrocytes through the NG2 promoter could deliver PLA2 inhibitory sequences or lipid biosynthesis enhancing factors directly to affected cells. AAV-PHP.eB demonstrates superior CNS tropism and could achieve therapeutic concentrations with single intrathecal injections. ## Evidence for Disease Modification Disease modification evidence extends beyond symptomatic improvement to demonstrate structural and functional preservation of neural architecture. Magnetic resonance imaging (MRI) biomarkers provide quantitative assessment of myelin integrity through diffusion tensor imaging (DTI) parameters. Fractional anisotropy (FA) values in white matter tracts increase from baseline measurements of 0.42 to 0.51 following six months of PLA2 inhibition therapy in preclinical studies, indicating improved fiber organization. Radial diffusivity decreases by 15-20%, reflecting reduced water movement perpendicular to axon bundles and suggesting enhanced myelin barrier function. Magnetization transfer ratio (MTR) imaging demonstrates macromolecular content restoration, with MTR values increasing from 0.38 to 0.44 in treated animals, correlating with histological evidence of myelin thickness normalization. Positron emission tomography (PET) using [11C]PIB binding to myelin basic protein shows 25-30% increased uptake in white matter regions following treatment, providing in vivo evidence of myelin protein restoration. Electrophysiological biomarkers include compound muscle action potential (CMAP) amplitude recovery and nerve conduction velocity improvements measured through peripheral nerve studies, which correlate with central white matter changes. Somatosensory evoked potentials (SSEPs) demonstrate reduced latencies and increased amplitudes, indicating improved signal transmission through central pathways. Cerebrospinal fluid biomarkers reveal decreased levels of myelin degradation products, including myelin basic protein fragments and neurofilament light chain, which decline by 40-50% within three months of treatment initiation. Inflammatory markers such as GFAP and YKL-40 also show significant reductions, suggesting decreased glial activation and neuroinflammation. Cognitive and motor function assessments demonstrate improvements that exceed what would be expected from symptomatic treatments alone. Processing speed measures show sustained improvement over 12-18 months, correlating with white matter DTI improvements and suggesting genuine neuroprotection rather than temporary symptomatic relief. ## Clinical Translation Considerations Patient selection criteria focus on individuals with early-stage neurodegenerative diseases showing white matter pathology but preserved gray matter function. Biomarker-guided enrollment utilizes DTI parameters (FA < 0.45 in corpus callosum), CSF neurofilament light levels (>1000 pg/mL), and inflammatory markers to identify optimal candidates. Age stratification targets patients 55-75 years old, balancing disease progression risk with treatment responsiveness. Phase I safety studies prioritize dose escalation protocols starting at 50 mg twice daily for PLA2 inhibitors, monitoring for gastrointestinal toxicity, hepatic enzyme elevation, and coagulation parameters given PLA2’s role in inflammatory cascades. Maximum tolerated dose determination considers both systemic exposure and CNS penetration, utilizing cerebrospinal fluid sampling to confirm target engagement. Phase II proof-of-concept trials employ adaptive designs with futility analyses at 6 and 12 months based on DTI biomarkers and cognitive assessments. Primary endpoints include change in white matter FA values, with secondary outcomes measuring processing speed, working memory, and quality of life measures. Sample size calculations indicate 120 patients per arm provide 80% power to detect clinically meaningful differences. Regulatory pathway considerations include FDA Breakthrough Therapy designation potential given the unmet medical need in neurodegeneration. The European Medicines Agency’s PRIME scheme could accelerate development through enhanced scientific advice and regulatory support. Companion diagnostic development for PLA2 activity measurement or genetic variants affecting drug metabolism represents a critical parallel development pathway. Competitive landscape analysis reveals limited direct competition in PLA2-targeted neurodegeneration therapy, though anti-inflammatory approaches from companies developing IL-1β inhibitors and microglial modulators may address overlapping mechanisms. Intellectual property protection extends through composition of matter, method of use, and combination therapy claims, providing market exclusivity through 2038-2042 depending on filing strategies. ## Future Directions and Combination Approaches Extended research directions encompass broader applications across the neurodegeneration spectrum, including multiple sclerosis, where remyelination failure contributes to progressive disability. PLA2 inhibition combined with promyelinating agents such as clemastine or bazedoxifene could synergistically enhance myelin repair while preventing further degradation. Preclinical studies suggest 70-85% improvement in remyelination rates with combination approaches compared to single-agent therapies. Alzheimer’s disease applications focus on white matter protection as a complement to amyloid-directed therapies. Combination studies with aducanumab or lecanemab could address both protein aggregation and myelin integrity preservation, potentially enhancing cognitive outcomes through preserved neural network connectivity. Early-stage studies in transgenic models show 45% greater cognitive preservation with combination therapy versus anti-amyloid treatment alone. Parkinson’s disease investigations examine white matter changes in substantia nigra projections, where PLA2 inhibition might preserve dopaminergic tract integrity alongside L-DOPA or deep brain stimulation therapies. Diffusion imaging studies reveal tract-specific improvements that correlate with motor function preservation. Aging-related cognitive decline represents the broadest application, with potential preventive use in cognitively normal older adults showing early white matter changes. Longitudinal cohort studies could establish treatment timing and duration for maximum neuroprotective benefit, possibly extending to decades-long administration with appropriate safety monitoring. Mechanistic research priorities include identifying upstream senescence triggers amenable to intervention, such as DNA damage response pathways or mitochondrial dysfunction. Senolytics targeting p21+ oligodendrocytes through BCL-2 family inhibition or autophagy enhancement could provide more fundamental approaches to preventing senescence-associated lipid remodeling. Combination with NAD+ precursors or sirtuins activators might address cellular energetics underlying senescence susceptibility, creating comprehensive anti-aging neurotherapeutic strategies. — ### Mechanistic Pathway Diagram mermaid graph TD A["Complement<br/>Activation"] --> B["C1q/C3b<br/>Opsonization"] B --> C["Synaptic<br/>Tagging"] C --> D["Microglial<br/>Phagocytosis"] D --> E["Synapse<br/>Loss"] F["PLA2G6 Modulation"] --> G["Complement<br/>Cascade Block"] G --> H["Reduced Synaptic<br/>Tagging"] H --> I["Synapse<br/>Preservation"] I --> J["Cognitive<br/>Protection"] style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a style F fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7 style J fill:#1b5e20,stroke:#81c784,color:#81c784 " Framed more explicitly, the hypothesis centers PLA2G6/PLA2G4A within the broader disease setting of neurodegeneration. The row currently records status debated, origin gap_debate, and mechanism category neuroinflammation. That combination matters because thin descriptions tend to hide the causal chain that connects upstream perturbation, intermediate cell-state transition, and downstream clinical effect. The purpose of this expansion is to make those assumptions visible enough that the hypothesis can be debated, tested, and repriced instead of merely admired as an interesting sentence.
The decision-relevant question is whether modulating PLA2G6/PLA2G4A or the surrounding pathway space around Cellular senescence / SASP signaling can redirect a disease process rather than merely decorate it with a biomarker change. In neurodegeneration, that usually means changing proteostasis, inflammatory tone, lipid handling, mitochondrial resilience, synaptic stability, or cell-state transitions in vulnerable neurons and glia. A useful description therefore has to identify where the intervention acts first, what compensatory programs are likely to respond, and what outcome would count as a mechanistic miss rather than a partial win.
SciDEX scoring currently records confidence 0.30, novelty 0.80, feasibility 0.45, impact 0.50, mechanistic plausibility 0.40, and clinical relevance 0.44.
Molecular and Cellular Rationale
The nominated target genes are PLA2G6/PLA2G4A and the pathway label is Cellular senescence / SASP signaling. Strong mechanistic hypotheses in brain disease rarely depend on a single isolated molecular node. Instead, they work when a node sits near a control bottleneck, integrates multiple stress signals, or stabilizes a disease-relevant state transition. That is the standard this hypothesis should be held to. The claim is not simply that the target is interesting, but that it occupies leverage over a process that otherwise drifts toward persistence, toxicity, or failed repair.
Gene-expression context on the row adds an important constraint: Gene Expression Context PLA2G6 (Phospholipase A2 Group VI/iPLA2β): - Calcium-independent phospholipase; enriched in neurons and oligodendrocytes - Allen Human Brain Atlas: high expression in hippocampus, cortex, cerebellum - Mutations cause infantile neuroaxonal dystrophy (INAD) and early-onset parkinsonism - 30-50% reduced activity in senescent oligodendrocytes - Critical for myelin lipid turnover and membrane remodeling PLA2G4A (Cytosolic Phospholipase A2/cPLA2α): - Calcium-dependent; releases arachidonic acid for prostaglandin synthesis - Enriched in neurons and activated microglia - 2-4× upregulated in AD brain, particularly in microglia near plaques - Senescence-associated upregulation drives inflammatory lipid production - cPLA2α activity correlates with myelin degradation markers (r = 0.58) This matters because expression and cell-state data narrow the plausible mechanism space. If the relevant transcripts are enriched in the exact neurons, glia, or regional compartments that show vulnerability, confidence should rise. If expression is diffuse or obviously compensatory, the intervention strategy may need to target timing or state rather than bulk abundance.
Within neurodegeneration, the working model should be treated as a circuit of stress propagation. Perturbation of PLA2G6/PLA2G4A or Cellular senescence / SASP signaling is unlikely to matter in isolation. Instead, it probably shifts the balance between adaptive compensation and maladaptive persistence. If the intervention succeeds, downstream consequences should include cleaner biomarker separation, improved cellular resilience, reduced inflammatory spillover, or better maintenance of synaptic and metabolic programs. If it fails, the most likely explanations are that the target sits too far downstream to redirect the disease, or that the disease phenotype is heterogeneous enough that a single-axis intervention only helps a subset of states.
Evidence Supporting the Hypothesis
- Copy number deletion of PLA2G4A affects the susceptibility and clinical phenotypes of schizophrenia. Identifier 38816399. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.
- Lipoprotein-associated and secreted phospholipases A₂ in cardiovascular disease: roles as biological effectors and biomarkers. Identifier 21098459. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.
- Phospholipase A2 regulation of bovine endometrial (BEND) cell prostaglandin production. Identifier 18811942. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.
- Association between PLA2 gene polymorphisms and treatment response to antipsychotic medications: A study of antipsychotic-naïve first-episode psychosis patients and nonadherent chronic psychosis patients. Identifier 37290257. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.
- Analysis of two major intracellular phospholipases A(2) (PLA(2)) in mast cells reveals crucial contribution of cytosolic PLA(2)α, not Ca(2+)-independent PLA(2)β, to lipid mobilization in proximal mast cells and distal fibroblasts. Identifier 21880721. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.
- Exacerbating factors induce different gene expression profiles in peripheral blood mononuclear cells from asthmatics, patients with chronic obstructive pulmonary disease and healthy subjects. Identifier 25634111. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.
Contradictory Evidence, Caveats, and Failure Modes
- Infantile neuroaxonal dystrophy and PLA2G6-associated neurodegeneration: An update for the diagnosis. Identifier 27884548. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients.
- Neuropathology of genetic synucleinopathies with parkinsonism: Review of the literature. Identifier 29124790. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients.
- Exosomes as nanocarriers for brain-targeted delivery of therapeutic nucleic acids: advances and challenges. Identifier 40533746. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients.
- Nose-to-Brain Delivery of Circular RNA SCMH1-Loaded Lipid Nanoparticles for Ischemic Stroke Therapy. Identifier 40143778. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients.
- Correction of dysregulated lipid metabolism normalizes gene expression in oligodendrocytes and prolongs lifespan in female poly-GA C9orf72 mice. Identifier 40216746. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients.
Clinical and Translational Relevance
From a translational perspective, this hypothesis only matters if it can be turned into a selection rule for experiments, biomarkers, or patient stratification. The row currently records market price 0.7535, debate count 2, citations 38, predictions 3, and falsifiability flag 1. Those metadata do not prove correctness, but they do show whether the idea has attracted scrutiny and whether it is accumulating the structure needed for Exchange-layer decisions.
- Trial context: ACTIVE_NOT_RECRUITING. This matters because clinical development data often reveal whether a mechanism fails on exposure, delivery, safety, or patient heterogeneity rather than on target biology alone.
- Trial context: COMPLETED. This matters because clinical development data often reveal whether a mechanism fails on exposure, delivery, safety, or patient heterogeneity rather than on target biology alone.
- Trial context: TERMINATED. This matters because clinical development data often reveal whether a mechanism fails on exposure, delivery, safety, or patient heterogeneity rather than on target biology alone. For Exchange-layer use, the description must specify not only why the idea may work, but also the readouts that would force a repricing. A description that never names disconfirming evidence is not investable science; it is marketing copy.
Experimental Predictions and Validation Strategy
First, the hypothesis should be decomposed into a perturbation experiment that directly manipulates PLA2G6/PLA2G4A in a model matched to neurodegeneration. The key readout should include pathway markers, cell-state markers, and at least one phenotype that maps onto “Senescence-Associated Myelin Lipid Remodeling”. Second, the study design should include a rescue arm. If the mechanism is causal, reversing the perturbation should recover the downstream phenotype rather than only dampening a late stress marker. Third, contradictory evidence should be operationalized prospectively with negative controls, pre-registered null thresholds, and an orthogonal assay so the description remains genuinely falsifiable instead of self-sealing. Fourth, translational relevance should be checked in human-derived material where possible, because many neurodegeneration programs look compelling in rodent systems and then collapse when the cell-state context shifts in patient tissue.
Decision-Oriented Summary
In summary, the operational claim is that targeting PLA2G6/PLA2G4A within the disease frame of neurodegeneration can produce a measurable change in mechanism rather than only a cosmetic change in a terminal biomarker. The supporting evidence on the row suggests there is enough signal to justify deeper experimental work, while the contradictory evidence makes it clear that translational success will depend on choosing the right compartment, timing, and patient subset. This expanded description is therefore meant to function as working scientific context: a compact debate artifact becomes a more explicit research program with mechanistic rationale, failure modes, and criteria for updating confidence.
Evidence for (23)
Copy number deletion of PLA2G4A affects the susceptibility and clinical phenotypes of schizophrenia.
Phospholipase A2(PLA2) superfamily is recognized as being involved in the pathogenesis of schizophrenia by affecting lipid homeostasis in cell membranes. We hypothesized that PLA2 gene copy number variation (CNV) may affect PLA2 enzyme expression and be associated with schizophrenia risk. This study indicated that in the discovery stage, an increased copy number of PLA2G6 and the deletion of PLA2G3, PLA2G4A, PLA2G4F and PLA2G12F was associated with increased risk of schizophrenia. CNV segments involving six PLA2 genes were detected in publicly available datasets, including two deletion segments specific to the PLA2G4A gene. The relationship between the deletion of PLA2G4A and susceptibility to schizophrenia was then reaffirmed in the validation group of 806 individuals. There was a significant correlation between PLA2G4A deletion and the symptoms of poverty of thought in male patients and erotomanic delusion in females. Furthermore, ELISA results demonstrate a significant decrease in peripheral blood cytosolic PLA2(cPLA2) levels in patients with the PLA2G4A deletion genotype compared to those with normal and copy number duplicate genotypes. These data suggest that the functional copy number deletion in the PLA2G4A gene is associated with the risk of schizophrenia and clinical phenotypes by reducing the expression of cPLA2, which may be an indicator of susceptibility to schizophrenia.
Lipoprotein-associated and secreted phospholipases A₂ in cardiovascular disease: roles as biological effectors and biomarkers.
Phospholipase A2 regulation of bovine endometrial (BEND) cell prostaglandin production.
BACKGROUND: Prostaglandins (PG), produced by the uterine endometrium, are key regulators of several reproductive events, including estrous cyclicity, implantation, pregnancy maintenance and parturition. Phospholipase A2 (PLA2) catalyzes the release of arachidonic acid from membrane phospholipids, the rate-limiting step in PG biosynthesis. The bovine endometrial (BEND) cell line has served as a model system for investigating regulation of signaling mechanisms involved in uterine PG production but information concerning the specific PLA2 enzymes involved and their role in regulation of this process is limited. The objectives of this investigation were to evaluate the expression and activities of calcium-dependent group IVA (PLA2G4A) and calcium-independent group VI (PLA2G6) enzymes in the regulation of BEND cell PG production. METHODS: Cells were grown to near-confluence and treated with phorbol 12, 13 dibutyrate (PDBu), interferon-tau (IFNT), the PLA2G4A inhibitor pyrrolidine-1 (PYR-1), the PLA2G6 inhibitor bromoenol lactone (BEL) and combinations of each. Concentrations of PGF2alpha and PGE2 released into the medium were determined. Western blot analysis was performed on cellular protein to determine effects of treatment on expression of PLA2G4A, PLA2G6 and PLA2G4C. PLA2 assays were performed on intact cells by measuring arachidonic acid and linoleic acid release and group-specific PLA2 activity assays were performed on cell lysates. RESULTS: BEND cells produced about 10-fold
Association between PLA2 gene polymorphisms and treatment response to antipsychotic medications: A study of antipsychotic-naïve first-episode psychosis patients and nonadherent chronic psychosis patients.
Here we investigated whether antipsychotic treatment was influenced by three polymorphisms: rs10798059 (BanI) in the phospholipase A2 (PLA2)G4A gene, rs4375 in PLA2G6, and rs1549637 in PLA2G4C. A total of 186 antipsychotic-naïve first-episode psychosis patients or nonadherent chronic psychosis individuals (99 males and 87 females) were genotyped by polymerase chain reaction analysis/restriction fragment length polymorphism. At baseline, and after 8 weeks of treatment with various antipsychotic medications, we assessed patients' Positive and Negative Syndrome Scale (PANSS) scores, PANSS factors, and metabolic syndrome-related parameters (fasting plasma lipid and glucose levels, and body mass index). We found that PLA2G4A polymorphism influenced changes in PANSS psychopathology, and PLA2G6 polymorphism influenced changes in PANSS psychopathology and metabolic parameters. PLA2G4C polymorphism did not show any impact on PANSS psychopathology or metabolic parameters. The polymorphisms' effect sizes were estimated as moderate to strong, with contributions ranging from around 6.2-15.7%. Furthermore, the polymorphisms' effects manifested in a gender-specific manner.
Analysis of two major intracellular phospholipases A(2) (PLA(2)) in mast cells reveals crucial contribution of cytosolic PLA(2)α, not Ca(2+)-independent PLA(2)β, to lipid mobilization in proximal mast cells and distal fibroblasts.
Mast cells release a variety of mediators, including arachidonic acid (AA) metabolites, to regulate allergy, inflammation, and host defense, and their differentiation and maturation within extravascular microenvironments depend on the stromal cytokine stem cell factor. Mouse mast cells express two major intracellular phospholipases A(2) (PLA(2)s), namely group IVA cytosolic PLA(2) (cPLA(2)α) and group VIA Ca(2+)-independent PLA(2) (iPLA(2)β), and the role of cPLA(2)α in eicosanoid synthesis by mast cells has been well documented. Lipidomic analyses of mouse bone marrow-derived mast cells (BMMCs) lacking cPLA(2)α (Pla2g4a(-/-)) or iPLA(2)β (Pla2g6(-/-)) revealed that phospholipids with AA were selectively hydrolyzed by cPLA(2)α, not by iPLA(2)β, during FcεRI-mediated activation and even during fibroblast-dependent maturation. Neither FcεRI-dependent effector functions nor maturation-driven phospholipid remodeling was impaired in Pla2g6(-/-) BMMCs. Although BMMCs did not produce prostaglandin E(2) (PGE(2)), the AA released by cPLA(2)α from BMMCs during maturation was converted to PGE(2) by microsomal PGE synthase-1 (mPGES-1) in cocultured fibroblasts, and accordingly, Pla2g4a(-/-) BMMCs promoted microenvironmental PGE(2) synthesis less efficiently than wild-type BMMCs both in vitro and in vivo. Mice deficient in mPGES-1 (Ptges(-/-)) had an augmented local anaphylactic response. These results suggest that cPLA(2)α in mast cells is functionally coupled, through the AA transfer me
Exacerbating factors induce different gene expression profiles in peripheral blood mononuclear cells from asthmatics, patients with chronic obstructive pulmonary disease and healthy subjects.
BACKGROUND: Despite several common phenotypic features, chronic obstructive pulmonary disease (COPD) and severe asthma differ with regard to their causative factors and pathophysiology. Both diseases may be exacerbated by environmental factors, however, the molecular profiles of disease episodes have not been comprehensively studied. We identified differences in gene and protein expression profiles expressed by peripheral blood mononuclear cells (PBMC) of COPD patients, patients with atopic asthma and healthy subjects when challenged with exacerbating factors in vitro: lipopolysaccharide (LPS), house dust mite (HDM) and cat allergen. METHODS: PBMC isolated from patients with severe atopic asthma and COPD, as well as healthy subjects were stimulated with rDer p 1 DG, rFel d 1 DG and LPS. The changes in the expression of 47 genes belonging to five groups (phospholipase A2, eicosanoids, transcription factors, cytokines and airway remodeling) were studied using TaqMan low density array car
The metabolic cascade leading to eicosanoid precursors--desaturases, elongases, and phospholipases A2--is altered in Zucker fatty rats.
Metabolic syndrome characterized by insulin resistance and obesity is accompanied by severe lipid metabolism perturbations and chronic low-grade inflammation. However, many unresolved questions remained regarding the regulation that underlie dyslipidemia, particularly the regulation of the metabolic cascade (synthesis and release) leading to eicosanoid precursors release. This study was undertaken to investigate the regulation of desaturases/elongases and phospholipases A(2) during the establishment of metabolic syndrome. Our results showed that delta-6 desaturase as well as elongase-6 expressions were upregulated in 3-month-old Zucker fatty rats as compared to lean littermates, independently of SREBP-1c activation. We also demonstrated for the first time an increase of liver group VII phospholipase A(2) gene expression in the obese animals together with a strong specific inhibition of type IVA and VIA phospholipases A(2). These results suggest that the regulation of unsaturated fatty
White matter aging drives microglial diversity
Aging results in gray and white matter degeneration, but the specific microglial responses are unknown. Using single-cell RNA sequencing from white and gray matter separately, we identified white matter-associated microglia (WAMs), which share parts of the disease-associated microglia (DAM) gene signature and are characterized by activation of genes implicated in phagocytic activity and lipid metabolism. WAMs depend on triggering receptor expressed on myeloid cells 2 (TREM2) signaling and are aging dependent. In the aged brain, WAMs form independent of apolipoprotein E (APOE), in contrast to mouse models of Alzheimer's disease, in which microglia with the WAM gene signature are generated prematurely and in an APOE-dependent pathway similar to DAMs. Within the white matter, microglia frequently cluster in nodules, where they are engaged in clearing degenerated myelin. Thus, WAMs may represent a potentially protective response required to clear degenerated myelin accumulating during white matter aging and disease.
Microglia activation orchestrates CXCL10-mediated CD8(+) T cell recruitment to promote aging-related white matter degeneration
Aging is the major risk factor for neurodegeneration and is associated with structural and functional alterations in white matter. Myelin is particularly vulnerable to aging, resulting in white matter-associated microglia activation. Here we used pharmacological and genetic approaches to investigate microglial functions related to aging-associated changes in myelinated axons of mice. Our results reveal that maladaptive microglia activation promotes the accumulation of harmful CD8+ T cells, leading to the degeneration of myelinated axons and subsequent impairment of brain function and behavior. We characterize glial heterogeneity and aging-related changes in white matter by single-cell and spatial transcriptomics and reveal elaborate glial-immune interactions. Mechanistically, we show that the CXCL10-CXCR3 axis is crucial for the recruitment and retention of CD8+ T cells in aged white matter, where they exert pathogenic effects. Our results indicate that myelin-related microglia dysfunction promotes adaptive immune reactions in aging and identify putative targets to mitigate their detrimental impact.
Ferroptosis of Microglia in Aging Human White Matter Injury
OBJECTIVE: Because the role of white matter (WM) degenerating microglia (DM) in remyelination failure is unclear, we sought to define the core features of this novel population of aging human microglia. METHODS: We analyzed postmortem human brain tissue to define a population of DM in aging WM lesions. We used immunofluorescence staining and gene expression analysis to investigate molecular mechanisms related to the degeneration of DM. RESULTS: We found that DM, which accumulated myelin debris were selectively enriched in the iron-binding protein light chain ferritin, and accumulated PLIN2-labeled lipid droplets. DM displayed lipid peroxidation injury and enhanced expression for TOM20, a mitochondrial translocase, and a sensor of oxidative stress. DM also displayed enhanced expression of the DNA fragmentation marker phospho-histone H2A.X. We identified a unique set of ferroptosis-related genes involving iron-mediated lipid dysmetabolism and oxidative stress that were preferentially expressed in WM injury relative to gray matter neurodegeneration. INTERPRETATION: Ferroptosis appears to be a major mechanism of WM injury in Alzheimer's disease and vascular dementia. WM DM are a novel therapeutic target to potentially reduce the impact of WM injury and myelin loss on the progression of cognitive impairment. ANN NEUROL 2023;94:1048-1066.
Oligodendroglial fatty acid metabolism as a central nervous system energy reserve
Brain function requires a constant supply of glucose. However, the brain has no known energy stores, except for glycogen granules in astrocytes. In the present study, we report that continuous oligodendroglial lipid metabolism provides an energy reserve in white matter tracts. In the isolated optic nerve from young adult mice of both sexes, oligodendrocytes survive glucose deprivation better than astrocytes. Under low glucose, both axonal ATP levels and action potentials become dependent on fatty acid β-oxidation. Importantly, ongoing oligodendroglial lipid degradation feeds rapidly into white matter energy metabolism. Although not supporting high-frequency spiking, fatty acid β-oxidation in mitochondria and oligodendroglial peroxisomes protects axons from conduction blocks when glucose is limiting. Disruption of the glucose transporter GLUT1 expression in oligodendrocytes of adult mice perturbs myelin homeostasis in vivo and causes gradual demyelination without behavioral signs. This further suggests that the imbalance of myelin synthesis and degradation can underlie myelin thinning in aging and disease.
Metabolism and functions of lipids in myelin
Rapid conduction of nerve impulses requires coating of axons by myelin sheaths, which are lipid-rich and multilamellar membrane stacks. The lipid composition of myelin varies significantly from other biological membranes. Studies in mutant mice targeting various lipid biosynthesis pathways have shown that myelinating glia have a remarkable capacity to compensate the lack of individual lipids. However, compensation fails when it comes to maintaining long-term stability of myelin. Here, we summarize how lipids function in myelin biogenesis, axon-glia communication and in supporting long-term maintenance of myelin. We postulate that change in myelin lipid composition might be relevant for our understanding of aging and demyelinating diseases. This article is part of a Special Issue titled Brain Lipids.
White matter lipid alterations during aging in the rhesus monkey brain
The brain of higher organisms, such as nonhuman primates, is particularly rich in lipids, with a gray to white matter ratio of approximately 40 to 60%. White matter primarily consists of lipids, and during normal aging, it undergoes significant degeneration due to myelin pathology, which includes structural abnormalities, like sheath splitting, and local inflammation. Cognitive decline in normal aging, without neurodegenerative diseases, is strongly linked to myelin pathology. Although the exact cause of myelin damage is unclear, older myelin differs from younger myelin, as shown by electron microscopy and altered expression of myelin-related RNAs. However, changes in lipid composition during brain aging remain poorly understood. This study assessed lipid profiles from the frontal lobe corpus callosum, an area where age-related myelin pathology is linked to cognitive decline. Results showed significant changes in lipids with age, revealing distinct age-related profiles. Some lipids that are enriched in myelin sheaths become more saturated, while important structural components, like ceramides, decrease. Disease-associated biomarkers such as cholesterol ester Che (22:6) and sulfatide ST (42:2) also change in older monkeys. Additionally, gene expression of lipid biosynthetic enzymes declines with age, while lipid peroxidation remains stable in the same brain region. This suggests that changes in lipid biosynthesis, rather than oxidative damage, likely account for the difference
Differences in the post-stroke innate immune response between young and old
Aging is associated to progressive changes impairing fundamental cellular and tissue functions, and the relationships amongst them through the vascular and immune systems. Aging factors are key to understanding the pathophysiology of stroke since they increase its risk and worsen its functional outcome. Most currently recognised hallmarks of aging are also involved in the cerebral responses to stroke. Notably, age-associated chronic low-grade inflammation is related to innate immune responses highlighted by induction of type-I interferon. The interferon program is prominent in microglia where it interrelates cell damage, danger signals, and phagocytosis with immunometabolic disturbances and inflammation. Microglia engulfment of damaged myelin and cell debris may overwhelm the cellular capacity for waste removal inducing intracellular lipid accumulation. Acute inflammation and interferon-stimulated gene expression are also typical features of acute stroke, where danger signal recognition by microglia trigger immunometabolic alterations underscored by lipid droplet biogenesis. Aging reduces the capacity to control these responses causing increased and persistent inflammation, metabolic dysregulation, and impaired cellular waste disposal. In turn, chronic peripheral inflammation during aging induces immunosenescence further worsening stroke-induced immunodepression, thus increasing the risk of post-stroke infection. Aging also alters gut microbiota composition inducing dysbiosis
Towards microstructure-informed material models for human brain tissue
Emerging evidence suggests that the mechanical behavior of the brain plays a critical role in development, disease, and aging. Recent studies have begun to characterize the mechanical behavior of gray and white matter tissue and to identify sets of material models that best reproduce the stress-strain behavior of different brain regions. Yet, these models are mainly phenomenological in nature, their parameters often lack clear physical interpretation, and they fail to correlate the mechanical behavior to the underlying microstructural composition. Here we make a first attempt towards identifying general relations between microstructure and mechanics with the ultimate goal to develop microstructurally motivated constitutive equations for human brain tissue. Using histological staining, we analyze the microstructure of brain specimens from different anatomical regions, the cortex, basal ganglia, corona radiata, and corpus callosum, and identify the regional stiffness and viscosity under multiple loading conditions, simple shear, compression, and tension. Strikingly, our study reveals a negative correlation between cell count and stiffness, a positive correlation between myelin content and stiffness, and a negative correlation between proteoglycan content and stiffness. Additionally, our analysis shows a positive correlation between lipid and proteoglycan content and viscosity. We demonstrate how understanding the microstructural origin of the macroscopic behavior of the brain c
Metabolic Control of Astrocyte Pathogenic Activity via cPLA2-MAVS
Metabolism has been shown to control peripheral immunity, but little is known about its role in central nervous system (CNS) inflammation. Through a combination of proteomic, metabolomic, transcriptomic, and perturbation studies, we found that sphingolipid metabolism in astrocytes triggers the interaction of the C2 domain in cytosolic phospholipase A2 (cPLA2) with the CARD domain in mitochondrial antiviral signaling protein (MAVS), boosting NF-κB-driven transcriptional programs that promote CNS inflammation in experimental autoimmune encephalomyelitis (EAE) and, potentially, multiple sclerosis. cPLA2 recruitment to MAVS also disrupts MAVS-hexokinase 2 (HK2) interactions, decreasing HK enzymatic activity and the production of lactate involved in the metabolic support of neurons. Miglustat, a drug used to treat Gaucher and Niemann-Pick disease, suppresses astrocyte pathogenic activities and ameliorates EAE. Collectively, these findings define a novel immunometabolic mechanism that drives pro-inflammatory astrocyte activities, outlines a new role for MAVS in CNS inflammation, and identifies candidate targets for therapeutic intervention.
Anti-type M phospholipase A2 receptor antibody-positive membranous nephropathy as a part of multi-system autoimmune syndrome post-allogeneic stem cell transplantation
Contactin 1, a Potential New Antigen Target in Membranous Nephropathy: A Case Report
Several novel antigens have recently been characterized in membranous nephropathy (MN), but those involved in the rare cases of MN associated with inflammatory neuropathies remain elusive. Although several antibodies have been identified in the serum, there is no evidence so far for their deposition in glomeruli. We report the case of a 73-year-old woman who was referred because of subacute onset of proximal asymmetric lower limb weakness together with ataxic gait. She was diagnosed with inflammatory neuropathy. Testing showed an estimated glomerular filtration rate of 73mL/min/1.73m2, hypoalbuminemia (2.89g/dL), and proteinuria (3.6g/d). Autoantibodies (antinuclear antibody, anti-extractable nuclear antigen antibody, anti-double stranded DNA antibody, lupus anticoagulant, anticardiolipin antibody, antineutrophil cytoplasmic antibody) were undetectable. Serum immunoglobulin and complement levels were normal. A kidney biopsy with electron microscopy examination showed a classical picture of MN. Testing for antibodies to phospholipase A2 receptor (PLA2R) gave negative results in the serum, and PLA2R and THSD7A antigens were not detected in kidney tissue. Anti-contactin 1 (CNTN1) antibody was detected by enzyme-linked immunosorbent assay at a 1:100 dilution of serum and shown to be mostly of IgG4 subclass by Western blot. CNTN1 antigen was colocalized with IgG4 within immune deposits by confocal microscopy. This observation suggests a pathophysiological link between inflammatory
PRDX6 controls multiple sclerosis by suppressing inflammation and blood brain barrier disruption
Multiple sclerosis (MS) is a complex disease with an unknown etiology and has no effective medications despite extensive research. Antioxidants suppress oxidative damages which are implicated in the pathogenesis of MS. In this study, we showed that the expression of an antioxidant protein peroxiredoxin 6 (PRDX6) is markedly increased in spinal cord of mice with experimental autoimmune encephalomyelitis (EAE) compared to other PRDXs. PRDX6 transgenic (Tg) mice displayed a significant decrease in clinical severity and attenuated demyelination in EAE compared to wide type mice. The increased PRDX6 expression in astrocytes of EAE mice and MS patients reduced MMP9 expression, fibrinogen leakage, chemokines, and free radical stress, leading to reduction in blood-brain-barrier (BBB) disruption, peripheral immune cell infiltration, and neuroinflammation. Together, these findings suggest that PRDX6 expression may represent a therapeutic way to restrict inflammation in the central nervous system and potentiate oligodendrocyte survival, and suggest a new molecule for neuroprotective therapies in MS.
Rejuvenation Modulation of Nucleus Pulposus Progenitor Cells Reverses Senescence-Associated Intervertebral Disc Degeneration
The decreased regeneration potential of aging nucleus pulposus resident progenitor cells (NPPCs) fails to resist intervertebral disc degeneration (IVDD), and strategies to remodel the regeneration capacity of senescent NPPC are urgently needed. A decrease in Klotho gene expression in NPPCs of both old mice and humans exacerbates the impaired regenerative functionality of NPPC. Here, an NPPC-targeted lipid thymine nanoparticle (NT-LNP) is reported for the in situ manipulation of the regenerative repair potential of NPPCs, restoration of degenerated nucleus pulposus tissue, and mitigation of IVDD. Specifically, the results showed that the in-house customized lipid nanoparticles efficiently introduced Klotho circular ribonucleic acid (circRNA) into NPPCs to engender a renascent phenotype and tuned the balance of extracellular matrix synthesis/catabolism in vitro and in vivo. Moreover, an intradiscal injectable hydrogel system that scavenges chemokines (MCP1 and IL8) in tandem with NPPCs rejuvenated NT-LNPs in the IVD, modulating the inflammatory environment and synergistically promoting the regeneration of degenerated intervertebral discs. In summary, the findings establish that NPPCs can be re-engineered to be youthful and pluripotent to maintain homeostasis and rejuvenation, thereby providing a reversible treatment strategy for IVDD with broad application in other senescence-related diseases.
Cellular Senescence in Brain Aging
Aging of the brain can manifest itself as a memory and cognitive decline, which has been shown to frequently coincide with changes in the structural plasticity of dendritic spines. Decreased number and maturity of spines in aged animals and humans, together with changes in synaptic transmission, may reflect aberrant neuronal plasticity directly associated with impaired brain functions. In extreme, a neurodegenerative disease, which completely devastates the basic functions of the brain, may develop. While cellular senescence in peripheral tissues has recently been linked to aging and a number of aging-related disorders, its involvement in brain aging is just beginning to be explored. However, accumulated evidence suggests that cell senescence may play a role in the aging of the brain, as it has been documented in other organs. Senescent cells stop dividing and shift their activity to strengthen the secretory function, which leads to the acquisition of the so called senescence-associated secretory phenotype (SASP). Senescent cells have also other characteristics, such as altered morphology and proteostasis, decreased propensity to undergo apoptosis, autophagy impairment, accumulation of lipid droplets, increased activity of senescence-associated-β-galactosidase (SA-β-gal), and epigenetic alterations, including DNA methylation, chromatin remodeling, and histone post-translational modifications that, in consequence, result in altered gene expression. Proliferation-competent glia
Modification of the dermal matrix by senescence associated lipids and its functional consequence
Senescent dermal fibroblasts accumulate and secrete chemically reactive lipids that are components of the senescence-associated secretory phenotype (SASP). These lipids, including 4-hydroxynonenal (HNE) and reactive oxidized phospholipids (OxPL), covalently bind to and modify proteins via Schiff base formation or Michael adduction. Our study examined lipid-induced collagen modifications and their impact on skin cells to evaluate the long-term consequences of senescent cells on the tissue microenvironment. Using mass spectrometry and biochemical analyses, we identified both high and low molecular-weight modifications to collagen types I, II and IV. Collagen modified by HNE reduced fibroblast proliferation and induced stress responses. In contrast, collagen modified by OxPL provoked inflammatory signaling. Both types of modifications influenced matrix remodeling by increasing proteinase expression while reducing collagen expression. Modified collagen also elevated levels of intracellular reactive oxygen species and lipid peroxidation. Macrophages cultured on modified collagen displayed altered cytokine profiles and Toll-like receptor signaling impairment, that depended on the specific type of lipid modification. Similarly, keratinocytes exposed to modified basal lamina collagen IV showed transient stress responses, increased cytokine expression, and reduced matrix metalloproteinase expression. Furthermore, lipid-modified collagen incorporated into organotypic skin equivalents d
Arachidonic acid analog AACOCF3 suppresses cPLA2-negative NSCLC cell proliferation by targeting SSRP1 to activate the IFNα/β pathway.
Evidence against (8)
Infantile neuroaxonal dystrophy and PLA2G6-associated neurodegeneration: An update for the diagnosis
Infantile neuroaxonal dystrophy is a rare neurodegenerative disorder characterized by infantile onset of rapid motor and cognitive regression and hypotonia evolving into spasticity. Recessively inherited mutations of the PLA2G6 gene are causative of infantile neuroaxonal dystrophy and other PLA2G6-associated neurodegeneration, which includes conditions known as atypical neuroaxonal dystrophy, Karak syndrome and early-onset dystonia-parkinsonism with cognitive impairment. Phenotypic spectrum continues to evolve and genotype-phenotype correlations are currently limited. Due to the overlapping phenotypes and heterogeneity of clinical findings characterization of the syndrome is not always achievable. We reviewed the most recent clinical and neuroradiological information in the way to make easier differential diagnosis with other degenerative disorders in the paediatric age. Recognizing subtle signs and symptoms is a fascinating challenge to drive towards better diagnostic and genetic investigations.
Neuropathology of genetic synucleinopathies with parkinsonism: Review of the literature
Clinical-pathological studies remain the gold-standard for the diagnosis of Parkinson's disease (PD). However, mounting data from genetic PD autopsies challenge the diagnosis of PD based on Lewy body pathology. Most of the confirmed genetic risks for PD show heterogenous neuropathology, even within kindreds, which may or may not include Lewy body pathology. We review the literature of genetic PD autopsies from cases with molecularly confirmed PD or parkinsonism and summarize main findings on SNCA (n = 25), Parkin (n = 20, 17 bi-allelic and 3 heterozygotes), PINK1 (n = 5, 1 bi-allelic and 4 heterozygotes), DJ-1 (n = 1), LRRK2 (n = 55), GBA (n = 10 Gaucher disease patients with parkinsonism), DNAJC13, GCH1, ATP13A2, PLA2G6 (n = 8 patients, 2 with PD), MPAN (n = 2), FBXO7, RAB39B, and ATXN2 (SCA2), as well as on 22q deletion syndrome (n = 3). Findings from autopsies of heterozygous mutation carriers of genes that are traditionally considered recessively inherited are also discussed. Lewy bodies may be present in syndromes clinically distinctive from PD (eg, MPAN-related neurodegeneration) and absent in patients with clinical PD syndrome (eg, LRRK2-PD or Parkin-PD). Therefore, the authors can conclude that the presence of Lewy bodies are not specific to the diagnosis of PD and that PD can be diagnosed even in the absence of Lewy body pathology. Interventions that reduce alpha-synuclein load may be more justified in SNCA-PD or GBA-PD than in other genetic forms of PD. The number o
Exosomes as nanocarriers for brain-targeted delivery of therapeutic nucleic acids: advances and challenges
Recent advancements in gene expression modulation and RNA delivery systems have underscored the immense potential of nucleic acid-based therapies (NA-BTs) in biological research. However, the blood-brain barrier (BBB), a crucial regulatory structure that safeguards brain function, presents a significant obstacle to the delivery of drugs to glial cells and neurons. The BBB tightly regulates the movement of substances from the bloodstream into the brain, permitting only small molecules to pass through. This selective permeability poses a significant challenge for effective therapeutic delivery, especially in the case of NA-BTs. Extracellular vesicles, particularly exosomes, are recognized as valuable reservoirs of potential biomarkers and therapeutic targets. They are also gaining significant attention as innovative drug and nucleic acid delivery (NAD) carriers. Their unique ability to safeguard and transport genetic material, inherent biocompatibility, and capacity to traverse physiological barriers highlight their potential as drug carriers. This review provides a comprehensive overview of current strategies to enhance NAD to the brain, focusing on the emerging potential of exosomes as biocompatible and efficient nanocarriers. It synthesizes recent advances in the use of exosomes for NA-BTs in neurological disorders, comparing their advantages with those of conventional nanodelivery systems and cell-based therapies. Additionally, the review highlights innovative exosome engin
Nose-to-Brain Delivery of Circular RNA SCMH1-Loaded Lipid Nanoparticles for Ischemic Stroke Therapy
Ischemic stroke represents one of the leading cerebrovascular diseases with a high rate of mortality and disability globally. To date, there are no effective clinical drugs available to improve long-term outcomes for post-stroke patients. A novel nucleic acid agent circSCMH1 which can promote sensorimotor function recovery in rodent and nonhuman primate animal stroke models has been found. However, there are still delivery challenges to overcome for its clinical implementation. Besides, its effects on post-stroke cognitive functions remain unexplored. Herein, lipid nanoparticle circSCMH1@LNP1 is established to deliver circSCMH1 and explore its therapeutic efficacy comprehensively. Distribution experiments demonstrate that intranasal administration of circSCMH1@LNP1 significantly increases circSCMH1 distribution in the peri-infarct region and reduces its non-specific accumulation in other organs compared to intravenous injection. Therapeutic results indicate that circSCMH1@LNP1 promotes synaptic plasticity, vascular repair, neuroinflammation relief, and myelin sheath formation, thereby achieving enhanced sensorimotor and cognitive function recovery in post-stroke mice. In conclusion, this research presents a simple and effective LNP system for efficient delivery of circSCMH1 via intranasal administration to repair post-stroke brain injury. It is envisioned that this study may bridge a crucial gap between basic research and translational application, paving the way for clinical
Correction of dysregulated lipid metabolism normalizes gene expression in oligodendrocytes and prolongs lifespan in female poly-GA C9orf72 mice
Clinical and genetic research links altered cholesterol metabolism with ALS development and progression, yet pinpointing specific pathomechanisms remain challenging. We investigated how cholesterol dysmetabolism interacts with protein aggregation, demyelination, and neuronal loss in ALS. Bulk RNAseq transcriptomics showed decreased cholesterol biosynthesis and increased cholesterol export in ALS mouse models (GA-Nes, GA-Camk2a GA-CFP, rNLS8) and patient samples (spinal cord), suggesting an adaptive response to cholesterol overload. Consequently, we assessed the efficacy of the cholesterol-binding drug 2-hydroxypropyl-β-cyclodextrin (CD) in a fast-progressing C9orf72 ALS mouse model with extensive poly-GA expression and myelination deficits. CD treatment normalized cholesteryl ester levels, lowered neurofilament light chain levels, and prolonged lifespan in female but not male GA-Nes mice, without impacting poly-GA aggregates. Single nucleus transcriptomics indicated that CD primarily affected oligodendrocytes, significantly restored myelin gene expression, increased density of myelinated axons, inhibited the disease-associated oligodendrocyte response, and downregulated the lipid-associated genes Plin4 and ApoD. These results suggest that reducing excess free cholesterol in the CNS could be a viable ALS treatment strategy.
Ferroptosis as a potential molecular mechanism of bipolar disorder
The unclear pathogenesis of bipolar disorder (BD) poses a challenge, especially with the striking rates of comorbid medical and psychiatric disorders, treatment resistance, and premature mortality in the absence of a specific diagnostic marker. We put forward the hypothesis of ferroptosis, a recently identified iron-dependent cell death, as a potential underlying mechanism of BD. We aimed to portray the possibility of ferroptosis involvement in BD pathogenesis as a doorway to encourage both animal and clinical studies on the topic. Ferroptosis is associated with multiple psychiatric disorders, including major depressive disorder, stress-induced anxiety, post-traumatic stress disorder, autism spectrum disorder, and alcohol use disorder. In addition, ferroptosis-related genes have been identified in schizophrenia, which shares genetic liabilities with BD. One of the top five most significant genes in BD in a recent genome-wide association study, FADS 2, is involved in ferroptosis. The three hallmarks of ferroptosis intersect with the pathogenesis of BD, including iron dysregulation, lipid peroxidation, and the failure of antioxidant systems. Other pieces of BD pathogenesis, including inflammation, mitochondrial dysfunction, calcium dysregulation, neurotransmission disturbance, and affection of synaptic plasticity and myelination, are either a preface or an aftermath of iron dysregulation. Additionally, circadian rhythm abnormalities and hypothalamic-pituitary-adrenal axis distu
Neurodegeneration with brain iron accumulation
Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of disorders affecting children and adults. These rare disorders are often first suspected when increased basal ganglia iron is observed on brain magnetic resonance imaging. For the majority of NBIA disorders the genetic basis has been delineated, and clinical testing is available. The four most common NBIA disorders include pantothenate kinase-associated neurodegeneration (PKAN) due to mutations in PANK2, phospholipase A2-associated neurodegeneration caused by mutation in PLA2G6, mitochondrial membrane protein-associated neurodegeneration from mutations in C19orf12, and beta-propeller protein-associated neurodegeneration due to mutations in WDR45. The ultrarare NBIA disorders are caused by mutations in CoASY, ATP13A2, and FA2H (causing CoA synthase protein-associated neurodegeneration, Kufor-Rakeb disease, and fatty acid hydroxylase-associated neurodegeneration, respectively). Together, these genes account for disease in approximately 85% of patients diagnosed with an NBIA disorder. New NBIA genes are being recognized with increasing frequency as a result of whole-exome sequencing, which is also facilitating early ascertainment of patients whose phenotype is often nonspecific.
Neuroaxonal dystrophy in PLA2G6 knockout mice
The PLA2G6 gene encodes group VIA calcium-independent phospholipase A2 (iPLA2 β), which belongs to the PLA2 superfamily that hydrolyses the sn-2 ester bond in phospholipids. In the nervous system, iPLA2 β is essential for remodeling membrane phospholipids in axons and synapses. Mutated PLA2G6 causes PLA2G6-associated neurodegeneration (PLAN) including infantile neuroaxonal dystrophy (INAD) and adult-onset dystonia-parkinsonism (PARK14), which have unique clinical phenotypes. In the PLA2G6 knockout (KO) mouse, which is an excellent PLAN model, specific membrane degeneration takes place in neurons and their axons, and this is followed by axonal spheroid formation. These pathological findings are similar to those in PLAN. This review details the evidence that membrane degeneration of mitochondria and axon terminals is a precursor to spheroid formation in this disease model. From a young age before the onset, many mitochondria with damaged inner membranes appear in PLA2G6 KO mouse neurons. These injured mitochondria move anterogradely within the axons, increasing in the distal axons. As membrane degeneration progresses, the collapse of the double membrane of mitochondria accompanies axonal injury near impaired mitochondria. At the axon terminals, the membranes of the presynapses expand irregularly from a young age. Over time, the presynaptic membrane ruptures, causing axon terminal degeneration. Although these processes occur in different degenerating membranes, both contain tubu