autophagy

Introduction

autophagy (from Greek “self-eating”) is a fundamental cellular degradation process that maintains cellular homeostasis by eliminating damaged organelles, misfolded proteins, and intracellular pathogens^{1Citation2011 · DOI 10.1016/j.cell.2011.10.026Open reference}. In neurons—post-mitotic cells that cannot divide and must survive for the entire lifespan—autophagy is particularly critical for maintaining proteostasis and cellular health^{2Citation2013 · DOI 10.1038/nm.3232Open reference}. The three primary forms of autophagy are macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA), each with distinct mechanisms and physiological roles^{3Citation2012 · DOI 10.1016/j.tcb.2012.05.006Open reference4Acetylation in the regulation of autophagy.2023 · Autophagy · DOI 10.1080/15548627.2022.2062112 · PMID 35435793Open reference}.

Macroautophagy (commonly referred to as “autophagy”) involves the formation of a double-membraned autophagosome that engulfs cytoplasmic cargo and delivers it to lysosomes for degradation^{5Citation2012 · DOI 10.4161/auto.19496Open reference}. This process is essential for the clearance of protein aggregates and damaged organelles that accumulate during aging and in neurodegenerative diseases^{6The roles of intracellular protein-degradation pathways in neurodegeneration2006 · DOI 10.1038/nature05291Open reference}. Microautophagy involves the direct engulfment of cytoplasmic material by lysosomal membrane invagination, while CMA involves the direct translocation of specific proteins containing a KFERQ motif across the lysosomal membrane via LAMP-2A^{7Citation2014 · DOI 10.1038/cr.2013.153Open reference}.

The autophagy-lysosome pathway is compromised in virtually all major neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s Disease, Huntington’s disease, and amyotrophic lateral sclerosis^{8Citation2015 · DOI 10.1038/nn.4030Open reference}. Dysfunction at multiple stages of the autophagy pathway—from autophagosome formation to lysosomal fusion and degradation—contributes to the accumulation of toxic protein aggregates that characterize these disorders^{9Citation2012 · DOI 10.1111/j.1742-4658.2011.08373.xOpen reference}. Understanding the molecular mechanisms underlying autophagy dysfunction has become a major focus for developing disease-modifying therapeutic strategies.

Pathway / Mechanism Diagram

graph TD
    A["Nutrient Deprivation / Stress"] --> B["AMPK Activation"]
    B --> C["ULK1 Complex Activation"]
    A --> D["mTORC1 Inhibition"]
    D --> C
    C --> E["Phagophore Nucleation (VPS34/Beclin-1)"]
    E --> F["LC3 Lipidation (LC3-II)"]
    F --> G["Autophagosome Formation"]
    G --> H["Cargo Recognition (p62/SQSTM1)"]
    H --> I["Autophagosome-Lysosome Fusion"]
    I --> J["Cargo Degradation"]
    J --> K["Amino Acid Recycling"]
    K --> L["Cell Survival"]
    M["Autophagy Impairment in Aging"] --> N["Aggregate Accumulation"]
    N --> O["Tau, Abeta, alpha-Synuclein Buildup"]
    O --> P["Neurodegeneration"]
    style L fill:#1b5e20,color:#e0e0e0
    style P fill:#ef5350,color:#e0e0e0
    style G fill:#006494,color:#e0e0e0

Molecular Mechanisms of autophagy

Autophagosome Formation

The formation of autophagosomes proceeds through a series of coordinated steps mediated by over 40 autophagy-related (ATG) proteins^{10The role of Atg proteins in autophagosome formation2011 · DOI 10.1146/annurev-cellbio-092910-154005Open reference}. This process is initiated by the ULK1 complex (comprising ULK1/2, ATG13, FIP200, and ATG101), which responds to cellular energy status via AMPK and nutrient availability via mTORC1^{2Citation2013 · DOI 10.1038/nm.3232Open reference}0. When nutrients are abundant, mTORC1 phosphorylates and inhibits the ULK1 complex; under starvation conditions, mTORC1 inhibition is released, allowing autophagosome nucleation^{2Citation2013 · DOI 10.1038/nm.3232Open reference}1.

The class III phosphoinositide 3-kinase (PI3K) complex (containing VPS34, VPS15, Beclin-1, and ATG14L) generates phosphatidylinositol 3-phosphate (PI3P) at the nascent autophagosome membrane, recruiting additional ATG proteins to the phagophore assembly site^{2Citation2013 · DOI 10.1038/nm.3232Open reference}2. Two ubiquitin-like conjugation systems are essential for autophagosome expansion: the ATG12-ATG5-ATG16L1 system and the LC3/GABARAP lipidation system^{2Citation2013 · DOI 10.1038/nm.3232Open reference}3. LC3 (microtubule-associated protein 1A/1B-light chain 3) is conjugated to phosphatidylethanolamine on the growing autophagosome membrane, facilitating cargo recognition and membrane expansion^{2Citation2013 · DOI 10.1038/nm.3232Open reference}4.

The closure of the autophagosome is mediated by the ESCRT machinery, which is also involved in endosomal and autophagosomal trafficking^{2Citation2013 · DOI 10.1038/nm.3232Open reference}5. Once closed, the autophagosome fuses with lysosomes to form autolysosomes, where the inner membrane and cargo are degraded by lysosomal hydrolases^{2Citation2013 · DOI 10.1038/nm.3232Open reference}6.

Selective autophagy

While bulk autophagy is typically induced by nutrient deprivation, selective autophagy specifically targets distinct cargoes including protein aggregates (aggrephagy), damaged mitochondria (mitophagy), peroxisomes (pexophagy), lipid droplets (lipophagy), and pathogens (xenophagy)^{2Citation2013 · DOI 10.1038/nm.3232Open reference}7. Selective autophagy is mediated by specific autophagy receptors that recognize cargo via ubiquitin tags and link them to LC3 on the autophagosome membrane^{2Citation2013 · DOI 10.1038/nm.3232Open reference}8.

The p62/SQSTM1 protein serves as a prototypic autophagy receptor, containing an N-terminal PB1 domain for oligomerization, a ZZ domain for ubiquitin binding, an LIR (LC3-interacting region) for LC3 binding, and a TBK1 phosphorylation site that enhances its autophagy activity^{2Citation2013 · DOI 10.1038/nm.3232Open reference}9. p62 body formation is a characteristic feature of many neurodegenerative diseases, representing failed attempts to clear ubiquitinated protein aggregates^{3Citation2012 · DOI 10.1016/j.tcb.2012.05.006Open reference}0.

NBR1 functions as an alternative autophagy receptor with distinct cargo specificity, while optineurin is particularly important for mitophagy, recognizing damaged mitochondria via ubiquitin chains and linking them to LC3^{3Citation2012 · DOI 10.1016/j.tcb.2012.05.006Open reference}1. The recognition of damaged mitochondria by Parkin and PINK1 represents a well-characterized mitophagy pathway that is defective in some forms of familial Parkinson’s Disease^{3Citation2012 · DOI 10.1016/j.tcb.2012.05.006Open reference}2.

Lysosomal Function

Lysosomes serve as the final destination for autophagic cargo degradation, and their proper function is essential for autophagy completion^{3Citation2012 · DOI 10.1016/j.tcb.2012.05.006Open reference}3. Lysosomes contain over 50 different hydrolases including cathepsins that degrade proteins, lipases that degrade lipids, and nucleases that degrade nucleic acids^{3Citation2012 · DOI 10.1016/j.tcb.2012.05.006Open reference}4. The lysosomal membrane is protected from degradation by a glycocalyx and specialized membrane proteins, while the acidic interior (pH 4.5-5.0) is maintained by vacuolar-type H+-ATPases^{3Citation2012 · DOI 10.1016/j.tcb.2012.05.006Open reference}5.

Lysosomal function is regulated by the transcription factor TFEB (Transcription Factor EB), which controls the expression of genes involved in autophagy and lysosomal biogenesis^{3Citation2012 · DOI 10.1016/j.tcb.2012.05.006Open reference}6. Under nutrient-rich conditions, TFEB is phosphorylated by mTORC1 and retained in the cytoplasm; upon starvation, TFEB translocates to the nucleus to activate the CLEAR (Coordinated Lysosomal Expression and Regulation) gene network^{3Citation2012 · DOI 10.1016/j.tcb.2012.05.006Open reference}7. This regulatory mechanism couples autophagy induction to lysosomal capacity.

The integrity of the autophagy-lysosome pathway is assessed by measuring autophagic flux—the complete process of autophagy from cargo sequestration to degradation^{3Citation2012 · DOI 10.1016/j.tcb.2012.05.006Open reference}8. Blockade at any step causes accumulation of autophagic intermediates and impairment of flux, which can be detected by analyzing LC3 turnover and p62 levels in the presence and absence of lysosomal inhibitors^{3Citation2012 · DOI 10.1016/j.tcb.2012.05.006Open reference}9.

autophagy in Neurodegenerative Diseases

Alzheimer’s disease

Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-beta plaques and tau neurofibrillary tangles, both of which are substrates for autophagy^{4Acetylation in the regulation of autophagy.2023 · Autophagy · DOI 10.1080/15548627.2022.2062112 · PMID 35435793Open reference}0. autophagy is highly active in neurons under normal conditions, and autophagic vacuoles accumulate prominently in AD brain tissue, particularly in dystrophic neurites surrounding amyloid plaques^{4Acetylation in the regulation of autophagy.2023 · Autophagy · DOI 10.1080/15548627.2022.2062112 · PMID 35435793Open reference}1. This accumulation reflects impaired autophagosome-lysosome fusion and lysosomal dysfunction rather than increased autophagosome formation^{4Acetylation in the regulation of autophagy.2023 · Autophagy · DOI 10.1080/15548627.2022.2062112 · PMID 35435793Open reference}2.

Multiple components of the autophagy pathway are altered in AD. Beclin-1 levels are reduced in AD brain, and genetic deletion of beclin-1 in mouse models enhances amyloid deposition^{4Acetylation in the regulation of autophagy.2023 · Autophagy · DOI 10.1080/15548627.2022.2062112 · PMID 35435793Open reference}3. The presenilin 1 mutations that cause familial AD impair lysosomal acidification and cathepsin activation, compromising the final degradative step of autophagy^{4Acetylation in the regulation of autophagy.2023 · Autophagy · DOI 10.1080/15548627.2022.2062112 · PMID 35435793Open reference}4. Tau pathology itself interferes with autophagosome trafficking by disrupting microtubule-based transport^{4Acetylation in the regulation of autophagy.2023 · Autophagy · DOI 10.1080/15548627.2022.2062112 · PMID 35435793Open reference}5.

Therapeutic strategies targeting autophagy in AD include mTOR inhibitors (rapamycin, temsirolimus), natural compounds that enhance autophagy (resveratrol, curcumin), and direct activators of TFEB^{4Acetylation in the regulation of autophagy.2023 · Autophagy · DOI 10.1080/15548627.2022.2062112 · PMID 35435793Open reference}6. Rapamycin treatment reduces amyloid pathology in mouse models, though clinical translation has been complicated by immunosuppressive effects^{4Acetylation in the regulation of autophagy.2023 · Autophagy · DOI 10.1080/15548627.2022.2062112 · PMID 35435793Open reference}7. The lysosomal enhancer gemfibrozil was identified in a screen as an inducer of TFEB and is being evaluated for AD treatment^{4Acetylation in the regulation of autophagy.2023 · Autophagy · DOI 10.1080/15548627.2022.2062112 · PMID 35435793Open reference}8.

Parkinson’s Disease

Parkinson’s Disease (PD) is characterized by the accumulation of alpha-synuclein in Lewy bodies and the degeneration of dopaminergic neurons in the substantia nigra^{4Acetylation in the regulation of autophagy.2023 · Autophagy · DOI 10.1080/15548627.2022.2062112 · PMID 35435793Open reference}9. autophagy plays a critical role in clearing alpha-synuclein, and impairment of this pathway contributes to its pathological accumulation^{5Citation2012 · DOI 10.4161/auto.19496Open reference}0. Both macroautophagy and chaperone-mediated autophagy are involved in alpha-synuclein degradation, and dysfunction in either pathway promotes alpha-synuclein aggregation^{5Citation2012 · DOI 10.4161/auto.19496Open reference}1.

Mutations causing familial PD provide insight into autophagy-pathology relationships. Loss-of-function mutations in PINK1 and PARKIN impair mitophagy, leading to accumulation of damaged mitochondria and increased oxidative stress^{5Citation2012 · DOI 10.4161/auto.19496Open reference}2. Mutations in GBA (glucocerebrosidase) impair lysosomal function and reduce CMA activity, increasing alpha-synuclein burden^{5Citation2012 · DOI 10.4161/auto.19496Open reference}3. LRRK2 mutations affect autophagic flux, and the G2019S mutation is the most common genetic cause of familial PD^{5Citation2012 · DOI 10.4161/auto.19496Open reference}4.

Enhancing autophagy represents a promising therapeutic approach for PD. The mTOR inhibitor rapamycin protects dopaminergic neurons in animal models, and the FDA-approved drug carbamazepine enhances autophagy and reduces alpha-synuclein toxicity^{5Citation2012 · DOI 10.4161/auto.19496Open reference}5. Small molecules that directly activate TFEB are in development for PD treatment^{5Citation2012 · DOI 10.4161/auto.19496Open reference}6.

Huntington’s Disease

Huntington’s disease (HD) is caused by CAG repeat expansion in the huntingtin (HTT) gene, leading to mutant huntingtin protein with an elongated polyglutamine tract that forms aggregates and is toxic to neurons^{5Citation2012 · DOI 10.4161/auto.19496Open reference}7. autophagy is responsible for clearing mutant huntingtin, and the polyglutamine expansion enhances its recognition as an autophagy substrate^{5Citation2012 · DOI 10.4161/auto.19496Open reference}8. However, autophagy is broadly impaired in HD, contributing to the accumulation of aggregates and cellular dysfunction^{5Citation2012 · DOI 10.4161/auto.19496Open reference}9.

The huntingtin protein itself regulates autophagy, and mutant huntingtin disrupts this function. Wild-type huntingtin acts as a scaffold for the autophagy machinery, facilitating cargo recognition and autophagosome formation^{6The roles of intracellular protein-degradation pathways in neurodegeneration2006 · DOI 10.1038/nature05291Open reference}0. Mutant huntingtin impairs this scaffolding function while also sequestering wild-type huntingtin into aggregates, creating a double hit to autophagic function^{6The roles of intracellular protein-degradation pathways in neurodegeneration2006 · DOI 10.1038/nature05291Open reference}1.

autophagy-inducing strategies show promise in HD models. mTOR-independent autophagy inducers including trehalose, minocycline, and lithium reduce mutant huntingtin aggregation and improve behavioral outcomes in mouse models^{6The roles of intracellular protein-degradation pathways in neurodegeneration2006 · DOI 10.1038/nature05291Open reference}2. The natural compound curcumin enhances autophagy and promotes the clearance of mutant huntingtin^{6The roles of intracellular protein-degradation pathways in neurodegeneration2006 · DOI 10.1038/nature05291Open reference}3.

Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of motor neurons, with protein aggregate accumulation in affected neurons^{6The roles of intracellular protein-degradation pathways in neurodegeneration2006 · DOI 10.1038/nature05291Open reference}4. autophagy is generally upregulated in ALS as a compensatory response, but the pathway is ultimately impaired by aggregate-mediated sequestration of autophagy proteins and disrupted lysosomal function^{6The roles of intracellular protein-degradation pathways in neurodegeneration2006 · DOI 10.1038/nature05291Open reference}5.

Mutations in several genes linked to familial ALS affect autophagy regulation. C9orf72 hexanucleotide repeat expansions are the most common genetic cause of ALS; the C9orf72 protein localizes to the phagophore assembly site and regulates autophagosome formation^{6The roles of intracellular protein-degradation pathways in neurodegeneration2006 · DOI 10.1038/nature05291Open reference}6. Mutations in SQSTM1 (encoding p62) cause familial ALS, and p62-positive aggregates are a hallmark of ALS pathology^{6The roles of intracellular protein-degradation pathways in neurodegeneration2006 · DOI 10.1038/nature05291Open reference}7. OPTN and TBK1 mutations also impair selective autophagy and cause ALS^{6The roles of intracellular protein-degradation pathways in neurodegeneration2006 · DOI 10.1038/nature05291Open reference}8.

Therapeutic approaches targeting autophagy in ALS include enhancing mitophagy to protect motor neurons from mitochondrial dysfunction and promoting the clearance of ALS-causing protein aggregates^{6The roles of intracellular protein-degradation pathways in neurodegeneration2006 · DOI 10.1038/nature05291Open reference}9. The small molecule SMER28 enhances autophagy and extends survival in animal models^{7Citation2014 · DOI 10.1038/cr.2013.153Open reference}0.

Therapeutic Modulation of autophagy

mTOR-Targeting Strategies

The mechanistic target of rapamycin (mTOR) is a central regulator of cell growth and autophagy. mTORC1 inhibition by rapamycin and its analogs induces autophagy by activating the ULK1 complex and releasing the inhibition of TFEB^{7Citation2014 · DOI 10.1038/cr.2013.153Open reference}1. This approach has shown efficacy in preclinical models of neurodegenerative disease but faces translational challenges due to the immunosuppressive and metabolic effects of chronic mTOR inhibition^{7Citation2014 · DOI 10.1038/cr.2013.153Open reference}2.

Second-generation mTOR inhibitors including Torin 1 and AZD8055 more completely inhibit both mTORC1 and mTORC2 and more potently induce autophagy^{7Citation2014 · DOI 10.1038/cr.2013.153Open reference}3. These compounds are being evaluated for neurodegenerative disease treatment, though dose-limiting toxicities remain a concern^{7Citation2014 · DOI 10.1038/cr.2013.153Open reference}4. Rapamycin analogs (rapalogs) with improved pharmacological properties are also in development^{7Citation2014 · DOI 10.1038/cr.2013.153Open reference}5.

mTOR-Independent Strategies

Multiple compounds induce autophagy through mTOR-independent mechanisms, offering potential advantages for therapeutic development. The cAMP phosphodiesterase inhibitor rolipram and the imidazoline receptor agonist TXM1 have been shown to enhance autophagy through distinct signaling pathways^{7Citation2014 · DOI 10.1038/cr.2013.153Open reference}6. These compounds may be particularly useful for diseases in which mTOR inhibition is contraindicated.

Natural products including resveratrol, curcumin, and epigallocatechin gallate (EGCG) enhance autophagy through multiple mechanisms, including sirtuin activation and AMPK signaling^{7Citation2014 · DOI 10.1038/cr.2013.153Open reference}7. These compounds have been extensively studied in neurodegenerative disease models and some have entered clinical trials, though bioavailability and target engagement remain challenges^{7Citation2014 · DOI 10.1038/cr.2013.153Open reference}8.

Lithium and valproic acid induce autophagy through inositol depletion, and this mechanism is independent of mTOR^{7Citation2014 · DOI 10.1038/cr.2013.153Open reference}9. These compounds have shown benefit in cellular and animal models of various neurodegenerative diseases and are being explored for clinical use^{8Citation2015 · DOI 10.1038/nn.4030Open reference}0.

autophagy Receptor Agonists

Direct targeting of autophagy receptors offers a more specific approach to enhancing selective autophagy. Small molecules that enhance p62 phosphorylation or interactions with LC3 could promote the clearance of specific cargoes^{8Citation2015 · DOI 10.1038/nn.4030Open reference}1. Similarly, mitophagy-inducing compounds that activate the PINK1-Parkin pathway or directly bind to mitophagy receptors are being developed for PD treatment^{8Citation2015 · DOI 10.1038/nn.4030Open reference}2.

TFEB agonists represent a promising approach that couples autophagy enhancement with lysosomal biogenesis^{8Citation2015 · DOI 10.1038/nn.4030Open reference}3. The natural compound genistein and the synthetic compound torin 2 activate TFEB, and these compounds show efficacy in preclinical models of neurodegenerative disease^{8Citation2015 · DOI 10.1038/nn.4030Open reference}4. The identification of brain-penetrant TFEB activators is an active area of research^{8Citation2015 · DOI 10.1038/nn.4030Open reference}5.

Lysosomal Enhancement

Given that lysosomal dysfunction is a common final pathway in neurodegenerative disease, strategies to enhance lysosomal function are of significant interest^{8Citation2015 · DOI 10.1038/nn.4030Open reference}6. Pharmacological chaperones that stabilize mutant lysosomal enzymes have shown promise for diseases including Gaucher disease and are being explored for related neurodegenerative conditions^{8Citation2015 · DOI 10.1038/nn.4030Open reference}7.

The TFEB transcription factor as discussed controls lysosomal biogenesis; TFEB overexpression enhances lysosomal capacity and promotes aggregate clearance in cellular models^{8Citation2015 · DOI 10.1038/nn.4030Open reference}8. Gene therapy approaches to deliver TFEB or enhance TFEB expression are in development, though careful attention to appropriate expression levels is required to avoid deleterious effects^{8Citation2015 · DOI 10.1038/nn.4030Open reference}9.

autophagy and Aging

Aging is associated with progressive decline in autophagy function across all tissues, and this decline contributes to the age-related accumulation of damaged proteins and organelles that characterizes aging and age-related diseases^{9Citation2012 · DOI 10.1111/j.1742-4658.2011.08373.xOpen reference}0. The molecular mechanisms underlying age-related autophagy decline include reduced expression of autophagy genes, impaired lysosomal function, and altered signaling through mTOR and AMPK^{9Citation2012 · DOI 10.1111/j.1742-4658.2011.08373.xOpen reference}1.

In the brain, age-related autophagy decline may be particularly significant given the post-mitotic nature of neurons and their inability to dilute damaged components through cell division^{9Citation2012 · DOI 10.1111/j.1742-4658.2011.08373.xOpen reference}2. The accumulation of lipofuscin (age pigment) in neurons is a hallmark of brain aging and reflects the failure of autophagy-lysosome pathways^{9Citation2012 · DOI 10.1111/j.1742-4658.2011.08373.xOpen reference}3.

Longevity interventions that extend lifespan in model organisms often involve autophagy enhancement. Caloric restriction, the most robust lifespan-extending intervention, strongly induces autophagy, and the beneficial effects of caloric restriction are at least partially dependent on autophagy^{9Citation2012 · DOI 10.1111/j.1742-4658.2011.08373.xOpen reference}4. Genetic manipulations that enhance autophagy extend lifespan in worms, flies, and mice, confirming the causal relationship between autophagy and longevity^{9Citation2012 · DOI 10.1111/j.1742-4658.2011.08373.xOpen reference}5.

Monitoring autophagy In Vivo

The assessment of autophagy in human brain tissue and peripheral tissues is challenging but essential for developing autophagy-targeted therapies^{9Citation2012 · DOI 10.1111/j.1742-4658.2011.08373.xOpen reference}6. autophagy biomarkers include LC3 lipidation (LC3-II) levels, p62 turnover, and autophagosome counts by electron microscopy^{9Citation2012 · DOI 10.1111/j.1742-4658.2011.08373.xOpen reference}7. Cerebrospinal fluid measurements of autophagy markers are being developed as minimally invasive biomarkers^{9Citation2012 · DOI 10.1111/j.1742-4658.2011.08373.xOpen reference}8.

Positron emission tomography (PET) tracers that target autophagy-related processes are in development, though no validated autophagic PET tracers are currently available for clinical use^{9Citation2012 · DOI 10.1111/j.1742-4658.2011.08373.xOpen reference}9. Magnetic resonance spectroscopy can detect changes in metabolite levels associated with autophagy modulation^{10The role of Atg proteins in autophagosome formation2011 · DOI 10.1146/annurev-cellbio-092910-154005Open reference}0.

Genomic and transcriptomic analyses of patient samples are providing insights into autophagy pathway dysregulation in neurodegenerative diseases^{10The role of Atg proteins in autophagosome formation2011 · DOI 10.1146/annurev-cellbio-092910-154005Open reference}1. These approaches have identified specific autophagy gene variants that modify disease risk and may inform patient selection for autophagy-targeted therapies^{10The role of Atg proteins in autophagosome formation2011 · DOI 10.1146/annurev-cellbio-092910-154005Open reference}2.

Conclusion

The autophagy-lysosome pathway plays a critical role in maintaining neuronal health, and its dysfunction is a common feature of virtually all neurodegenerative diseases. The accumulation of protein aggregates in these disorders reflects impaired autophagic clearance, and enhancing autophagy represents a promising therapeutic strategy. While challenges remain in achieving appropriate target engagement and avoiding adverse effects, multiple autophagy-modulating compounds are advancing through clinical development. A deeper understanding of the specific autophagy pathways impaired in each disease and the development of biomarkers to monitor target engagement will facilitate the successful translation of autophagy-targeted therapies to the clinic.