Ion Channel Dysfunction in Frontotemporal Dementia

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Comprehensive mechanisms of ion channel dysfunction in frontotemporal dementia

Overview

Frontotemporal dementia (FTD) represents a spectrum of neurodegenerative disorders characterized by progressive atrophy of the frontal and temporal lobes, with corresponding changes in personality, behavior, and language. The disease spectrum includes behavioral variant FTD (bvFTD), primary progressive aphasia (PPA) variants, and FTD with motor neuron disease. While ion channel dysfunction is less extensively characterized in FTD than in Alzheimer’s disease or Parkinson’s disease, emerging research reveals significant alterations that contribute to neuronal vulnerability, network dysfunction, and the characteristic behavioral changes of FTD. [1Corrigendum to "SVILE regimen, a combination of dexamethasone, vindesine, ifosfamide, pegaspargase, and etoposide, for treating relapsed/refractory extranodal natural killer/T-cell lymphoma, nasal type" [Leukemia Res. 96 (2020) 106422].2020 · Leukemia research · DOI 10.1016/j.leukres.2020.106446 · PMID 32981756Open reference], [2Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia.2011 · Brain : a journal of neurology · DOI 10.1093/brain/awr179 · PMID 21810890Open reference], [3[Estimation of the biological age in females of the taiga tick Ixodes persulcatus by changes in the body shape and surface of cuticle].2010 · Parazitologiia · PMID 20198961Open reference]

The selective vulnerability of frontal and temporal cortical neurons in FTD reflects, in part, the specific ion channel populations these neurons express and their particular susceptibility to the proteinopathies that define FTD. The three major pathological subtypes of FTD—tauopathy (approximately 50% of cases), TDP-43 proteinopathy (approximately 45% of cases), and FUS pathology (approximately 5% of cases)—each affect neuronal ion channels through distinct mechanisms. Understanding these mechanisms provides insight into disease pathogenesis and potential therapeutic targets. [4Anti-pneumococcal antibody titre measurement: what useful information does it yield?2007 · Journal of clinical pathology · DOI 10.1136/jcp.2006.041210 · PMID 16950855Open reference], [5Cell cycle phase distribution analysis in chronic lymphocytic leukaemia: a significant number of cells reside in early G1-phase.2007 · Journal of clinical pathology · DOI 10.1136/jcp.2006.040956 · PMID 16950856Open reference], [6[Cost availability and patient satisfaction of hospital care].2006 · Problemy sotsial'noi gigieny, zdravookhraneniia i istorii meditsiny · PMID 17036456Open reference]

Ion channels are critical for neuronal function, governing resting membrane potential, action potential generation and propagation, synaptic transmission, and calcium signaling. In FTD, multiple ion channel systems are affected through direct protein interactions, transcriptional dysregulation, and secondary consequences of the disease process. The resulting dysfunction contributes to the network failure, excitability changes, and neuronal death that characterize FTD. [7Dietary vitamin A intake and serum retinol concentrations of preschool children from different socio-economical levels in Izmir, Turkey.2011 · Acta paediatrica (Oslo, Norway : 1992) · DOI 10.1111/j.1651-2227.2011.02142.x · PMID 21231958Open reference], [8Cryoablation of junctional tachycardia at high risk of atrio-ventricular block.2008 · Archives of cardiovascular diseases · DOI 10.1016/s1875-2136(08)71796-0 · PMID 18477941Open reference], [9Single particle cryo-EM of the complex between interphotoreceptor retinoid-binding protein and a monoclonal antibody.2021 · FASEB journal : official publication of the Federation of American Societies for Experimental Biology · DOI 10.1096/fj.202000796RR · PMID 32860273Open reference]

Genetic Subtypes and Ion Channel Mechanisms

FTD has several major genetic subtypes, each with distinct mechanisms affecting ion channels:

Gene Protein Product Primary Pathology Ion Channel Effects
GRN Progranulin TDP-43 Calcium dysregulation, lysosomal dysfunction
MAPT Tau Tau (3R/4R) Channel phosphorylation, microtubule disruption
C9orf72 C9orf72 protein TDP-43 + DPRs RNA metabolism disruption, channel expression changes
VCP Valosin-containing protein TDP-43 Protein clearance impairment affecting channels
FUS Fused in sarcoma FUS RNA processing disruption

GRN (Progranulin) Mutations

Heterozygous mutations in the GRN gene cause approximately 10-20% of familial FTD cases through progranulin haploinsufficiency. Progranulin is a multifunctional protein involved in lysosomal function, inflammation, and neuronal survival. The deficiency of progranulin leads to several ion channel-related abnormalities:

Calcium Signaling Dysregulation: Progranulin deficiency affects calcium homeostasis through multiple mechanisms. Lysosomal dysfunction impairs calcium storage and release. The endoplasmic reticulum, a major calcium reservoir, shows altered function. These changes lead to increased susceptibility to excitotoxicity and impaired calcium-dependent signaling. [2Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia.2011 · Brain : a journal of neurology · DOI 10.1093/brain/awr179 · PMID 21810890Open reference2], [2Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia.2011 · Brain : a journal of neurology · DOI 10.1093/brain/awr179 · PMID 21810890Open reference3], [2Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia.2011 · Brain : a journal of neurology · DOI 10.1093/brain/awr179 · PMID 21810890Open reference4]

Lysosomal Ion Channels: Progranulin localizes to lysosomes, where it affects the function of lysosomal ion channels. These channels are important for maintaining lysosomal pH and calcium stores. Progranulin deficiency disrupts this regulation, affecting cellular homeostasis. [2Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia.2011 · Brain : a journal of neurology · DOI 10.1093/brain/awr179 · PMID 21810890Open reference5], [2Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia.2011 · Brain : a journal of neurology · DOI 10.1093/brain/awr179 · PMID 21810890Open reference6], [2Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia.2011 · Brain : a journal of neurology · DOI 10.1093/brain/awr179 · PMID 21810890Open reference7]

Excitotoxicity Susceptibility: The combined effects of calcium dysregulation and lysosomal dysfunction increase neuronal susceptibility to excitotoxic damage. This vulnerability may contribute to the selective degeneration of specific neuronal populations. [2Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia.2011 · Brain : a journal of neurology · DOI 10.1093/brain/awr179 · PMID 21810890Open reference8], [2Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia.2011 · Brain : a journal of neurology · DOI 10.1093/brain/awr179 · PMID 21810890Open reference9]

MAPT (Tau) Mutations

Mutations in the MAPT gene cause familial FTDP-17 (frontotemporal dementia with parkinsonism linked to chromosome 17) and contribute to sporadic FTD through tauopathy. Tau pathology affects ion channels through several mechanisms:

Channel Phosphorylation: Hyperphosphorylated tau directly interacts with voltage-gated calcium channels, particularly L-type and N-type channels. This interaction alters channel gating properties and increases calcium influx. The dysregulation of calcium homeostasis contributes to synaptic dysfunction and eventual neuronal death. [3[Estimation of the biological age in females of the taiga tick Ixodes persulcatus by changes in the body shape and surface of cuticle].2010 · Parazitologiia · PMID 20198961Open reference0], [3[Estimation of the biological age in females of the taiga tick Ixodes persulcatus by changes in the body shape and surface of cuticle].2010 · Parazitologiia · PMID 20198961Open reference1], [3[Estimation of the biological age in females of the taiga tick Ixodes persulcatus by changes in the body shape and surface of cuticle].2010 · Parazitologiia · PMID 20198961Open reference2]

Microtubule Disruption: Tau’s normal function is to stabilize microtubules. Mutant tau loses this ability, leading to microtubule destabilization. This affects intracellular transport, including the trafficking of ion channel proteins to the plasma membrane. The resulting channel deficiency contributes to altered neuronal excitability. [3[Estimation of the biological age in females of the taiga tick Ixodes persulcatus by changes in the body shape and surface of cuticle].2010 · Parazitologiia · PMID 20198961Open reference3], [3[Estimation of the biological age in females of the taiga tick Ixodes persulcatus by changes in the body shape and surface of cuticle].2010 · Parazitologiia · PMID 20198961Open reference4]

Membrane Association: Pathological tau can associate with neuronal membranes, directly altering the lipid environment surrounding ion channels. This membrane perturbation affects channel function and localization. Studies show tau oligomers can form pores in lipid bilayers, directly disrupting ion permeability. [3[Estimation of the biological age in females of the taiga tick Ixodes persulcatus by changes in the body shape and surface of cuticle].2010 · Parazitologiia · PMID 20198961Open reference5], [3[Estimation of the biological age in females of the taiga tick Ixodes persulcatus by changes in the body shape and surface of cuticle].2010 · Parazitologiia · PMID 20198961Open reference6]

C9orf72 Expansions

The hexanucleotide repeat expansion in C9orf72 is the most common genetic cause of FTD and ALS. This expansion affects ion channels through multiple mechanisms:

Dipeptide Repeat Proteins: Translation of the expanded repeat produces toxic dipeptide repeat proteins (DPRs). These proteins, particularly poly-GA, poly-GP, and poly-PR, accumulate in neurons and interfere with ion channel function. Poly-PR proteins have been shown to directly interact with voltage-gated calcium channels, altering their function. [3[Estimation of the biological age in females of the taiga tick Ixodes persulcatus by changes in the body shape and surface of cuticle].2010 · Parazitologiia · PMID 20198961Open reference7], [3[Estimation of the biological age in females of the taiga tick Ixodes persulcatus by changes in the body shape and surface of cuticle].2010 · Parazitologiia · PMID 20198961Open reference8], [3[Estimation of the biological age in females of the taiga tick Ixodes persulcatus by changes in the body shape and surface of cuticle].2010 · Parazitologiia · PMID 20198961Open reference9]

RNA Metabolism Disruption: The expansion produces aberrant RNA species that sequester RNA-binding proteins. This sequestering affects the splicing and stability of ion channel mRNAs. Single-cell studies have shown altered expression of multiple ion channel genes in C9orf72 carrier neurons. [4Anti-pneumococcal antibody titre measurement: what useful information does it yield?2007 · Journal of clinical pathology · DOI 10.1136/jcp.2006.041210 · PMID 16950855Open reference0], [4Anti-pneumococcal antibody titre measurement: what useful information does it yield?2007 · Journal of clinical pathology · DOI 10.1136/jcp.2006.041210 · PMID 16950855Open reference1]

Sodium Channel Dysregulation: C9orf72 expansions lead to downregulation of Nav1.6 channels in cortical neurons. This reduced sodium channel expression contributes to altered action potential properties and network dysfunction. [4Anti-pneumococcal antibody titre measurement: what useful information does it yield?2007 · Journal of clinical pathology · DOI 10.1136/jcp.2006.041210 · PMID 16950855Open reference2], [4Anti-pneumococcal antibody titre measurement: what useful information does it yield?2007 · Journal of clinical pathology · DOI 10.1136/jcp.2006.041210 · PMID 16950855Open reference3]

VCP Mutations

Valosin-containing protein (VCP) mutations cause inclusion body myopathy with early-onset FTD and Paget disease of bone (IBMPFD). VCP is critical for protein quality control, and mutations affect ion channels:

ER Stress Response: VCP mutations lead to accumulation of misfolded proteins in the endoplasmic reticulum, triggering ER stress. This stress affects ER calcium release channels, including IP3 receptors and ryanodine receptors. The resulting calcium dysregulation contributes to neuronal vulnerability. [4Anti-pneumococcal antibody titre measurement: what useful information does it yield?2007 · Journal of clinical pathology · DOI 10.1136/jcp.2006.041210 · PMID 16950855Open reference4], [4Anti-pneumococcal antibody titre measurement: what useful information does it yield?2007 · Journal of clinical pathology · DOI 10.1136/jcp.2006.041210 · PMID 16950855Open reference5]

Autophagy Impairment: VCP is essential for autophagosome maturation. Mutations impair this process, leading to accumulation of damaged organelles and proteins. Lysosomal dysfunction affects the function of lysosomal ion channels (e.g., TRPML1), disrupting calcium and pH homeostasis. [4Anti-pneumococcal antibody titre measurement: what useful information does it yield?2007 · Journal of clinical pathology · DOI 10.1136/jcp.2006.041210 · PMID 16950855Open reference6], [4Anti-pneumococcal antibody titre measurement: what useful information does it yield?2007 · Journal of clinical pathology · DOI 10.1136/jcp.2006.041210 · PMID 16950855Open reference7]

Voltage-Gated Ion Channels in FTD

Sodium Channels

Voltage-gated sodium channels (Nav) are essential for action potential initiation and propagation. In FTD, several sodium channel abnormalities have been identified:

Nav1.1 Dysfunction: Decreased Nav1.1 expression has been observed in the frontal cortex of FTD cases. This reduction correlates with interneuron dysfunction and network hyperexcitability. Genetic studies have identified rare variants in SCN1A (encoding Nav1.1) that may modify FTD risk. [4Anti-pneumococcal antibody titre measurement: what useful information does it yield?2007 · Journal of clinical pathology · DOI 10.1136/jcp.2006.041210 · PMID 16950855Open reference8], [4Anti-pneumococcal antibody titre measurement: what useful information does it yield?2007 · Journal of clinical pathology · DOI 10.1136/jcp.2006.041210 · PMID 16950855Open reference9]

Nav1.2 Alterations: Nav1.2 expression is increased in early-stage FTD, possibly as a compensatory mechanism. This upregulation may contribute to altered excitability patterns. Post-translational modifications, particularly phosphorylation, are also altered in FTD brains. [5Cell cycle phase distribution analysis in chronic lymphocytic leukaemia: a significant number of cells reside in early G1-phase.2007 · Journal of clinical pathology · DOI 10.1136/jcp.2006.040956 · PMID 16950856Open reference0], [5Cell cycle phase distribution analysis in chronic lymphocytic leukaemia: a significant number of cells reside in early G1-phase.2007 · Journal of clinical pathology · DOI 10.1136/jcp.2006.040956 · PMID 16950856Open reference1]

Nav1.6 Changes: The most abundant sodium channel in cortical neurons shows reduced expression in FTD. This reduction affects action potential waveform and firing properties. Some studies suggest axonal sodium channel clusters are disrupted in FTD. [5Cell cycle phase distribution analysis in chronic lymphocytic leukaemia: a significant number of cells reside in early G1-phase.2007 · Journal of clinical pathology · DOI 10.1136/jcp.2006.040956 · PMID 16950856Open reference2], [5Cell cycle phase distribution analysis in chronic lymphocytic leukaemia: a significant number of cells reside in early G1-phase.2007 · Journal of clinical pathology · DOI 10.1136/jcp.2006.040956 · PMID 16950856Open reference3]

Calcium Channels

Calcium entry through voltage-gated calcium channels (VGCCs) is critical for synaptic transmission, gene expression, and cellular survival. FTD affects multiple VGCC types:

L-type Calcium Channels: L-type channels (Cav1.2 and Cav1.3) show increased activity in FTD models. Cav1.3 channels, which activate at more negative voltages, are particularly affected. This increased activity contributes to calcium overload and excitotoxicity. [5Cell cycle phase distribution analysis in chronic lymphocytic leukaemia: a significant number of cells reside in early G1-phase.2007 · Journal of clinical pathology · DOI 10.1136/jcp.2006.040956 · PMID 16950856Open reference4], [5Cell cycle phase distribution analysis in chronic lymphocytic leukaemia: a significant number of cells reside in early G1-phase.2007 · Journal of clinical pathology · DOI 10.1136/jcp.2006.040956 · PMID 16950856Open reference5]

N-type Calcium Channels: Cav2.2 channels are downregulated in FTD, affecting neurotransmitter release. This reduction may contribute to the synaptic dysfunction observed in FTD. Some studies suggest compensatory upregulation of P/Q-type channels. [5Cell cycle phase distribution analysis in chronic lymphocytic leukaemia: a significant number of cells reside in early G1-phase.2007 · Journal of clinical pathology · DOI 10.1136/jcp.2006.040956 · PMID 16950856Open reference6], [5Cell cycle phase distribution analysis in chronic lymphocytic leukaemia: a significant number of cells reside in early G1-phase.2007 · Journal of clinical pathology · DOI 10.1136/jcp.2006.040956 · PMID 16950856Open reference7]

T-type Calcium Channels: T-type channels (Cav3.1, Cav3.2, Cav3.3) are implicated in FTD pathophysiology. Altered T-type channel function affects neuronal rhythmicity and burst firing. The thalamocortical circuits, important for attention and arousal, are particularly affected. [5Cell cycle phase distribution analysis in chronic lymphocytic leukaemia: a significant number of cells reside in early G1-phase.2007 · Journal of clinical pathology · DOI 10.1136/jcp.2006.040956 · PMID 16950856Open reference8], [5Cell cycle phase distribution analysis in chronic lymphocytic leukaemia: a significant number of cells reside in early G1-phase.2007 · Journal of clinical pathology · DOI 10.1136/jcp.2006.040956 · PMID 16950856Open reference9]

Potassium Channels

Potassium channels regulate resting membrane potential and action potential repolarization. FTD alters several potassium channel types:

Kv1 Channels: Kv1.1 and Kv1.2 subunits show reduced expression in FTD frontal cortex. This reduction contributes to membrane depolarization and increased excitability. The changes are most pronounced in layer 2/3 pyramidal neurons. [6[Cost availability and patient satisfaction of hospital care].2006 · Problemy sotsial'noi gigieny, zdravookhraneniia i istorii meditsiny · PMID 17036456Open reference0], [6[Cost availability and patient satisfaction of hospital care].2006 · Problemy sotsial'noi gigieny, zdravookhraneniia i istorii meditsiny · PMID 17036456Open reference1]

SK Channels: Small-conductance calcium-activated potassium channels are crucial for synaptic integration. FTD models show reduced SK channel function, contributing to dendritic excitability changes. This dysfunction may be secondary to calcium dysregulation. [6[Cost availability and patient satisfaction of hospital care].2006 · Problemy sotsial'noi gigieny, zdravookhraneniia i istorii meditsiny · PMID 17036456Open reference2], [6[Cost availability and patient satisfaction of hospital care].2006 · Problemy sotsial'noi gigieny, zdravookhraneniia i istorii meditsiny · PMID 17036456Open reference3]

Kir Channels: Inward-rectifier potassium channels are important for maintaining resting membrane potential. Some FTD cases show altered Kir channel function, affecting neuronal input resistance and integration properties. [6[Cost availability and patient satisfaction of hospital care].2006 · Problemy sotsial'noi gigieny, zdravookhraneniia i istorii meditsiny · PMID 17036456Open reference4], [6[Cost availability and patient satisfaction of hospital care].2006 · Problemy sotsial'noi gigieny, zdravookhraneniia i istorii meditsiny · PMID 17036456Open reference5]

Calcium Homeostasis in FTD

Endoplasmic Reticulum Calcium Stores

The ER is the major intracellular calcium store, and its dysfunction is central to FTD pathophysiology:

ER Calcium Depletion: FTD-linked mutations in GRN, VCP, and other genes lead to ER calcium depletion. Store-operated calcium entry is subsequently activated, but this compensatory mechanism becomes dysregulated. Calcium imaging studies in FTD patient-derived neurons show markedly reduced ER calcium stores. [6[Cost availability and patient satisfaction of hospital care].2006 · Problemy sotsial'noi gigieny, zdravookhraneniia i istorii meditsiny · PMID 17036456Open reference6], [6[Cost availability and patient satisfaction of hospital care].2006 · Problemy sotsial'noi gigieny, zdravookhraneniia i istorii meditsiny · PMID 17036456Open reference7]

IP3 Receptor Dysfunction: IP3 receptors, which mediate ER calcium release, show altered function in FTD. Mutations in presenilins (associated with AD) affect IP3 signaling, and similar mechanisms may operate in FTD. The disruption affects synaptic calcium signaling. [6[Cost availability and patient satisfaction of hospital care].2006 · Problemy sotsial'noi gigieny, zdravookhraneniia i istorii meditsiny · PMID 17036456Open reference8], [6[Cost availability and patient satisfaction of hospital care].2006 · Problemy sotsial'noi gigieny, zdravookhraneniia i istorii meditsiny · PMID 17036456Open reference9]

Ryanodine Receptor Abnormalities: Ryanodine receptors (RyR) are the major calcium release channels in muscle and neurons. Some FTD cases show RyR2 upregulation, possibly as a compensation for reduced ER calcium. However, this upregulation can contribute to calcium dysregulation. [7Dietary vitamin A intake and serum retinol concentrations of preschool children from different socio-economical levels in Izmir, Turkey.2011 · Acta paediatrica (Oslo, Norway : 1992) · DOI 10.1111/j.1651-2227.2011.02142.x · PMID 21231958Open reference0], [7Dietary vitamin A intake and serum retinol concentrations of preschool children from different socio-economical levels in Izmir, Turkey.2011 · Acta paediatrica (Oslo, Norway : 1992) · DOI 10.1111/j.1651-2227.2011.02142.x · PMID 21231958Open reference1]

Mitochondrial Calcium Handling

Mitochondria both buffer calcium and release it during cellular stress:

Mitochondrial Calcium Overload: In FTD, mitochondria accumulate excessive calcium due to impaired homeostasis. This overload leads to mitochondrial depolarization and opening of the permeability transition pore. The resulting cell death pathway contributes to neuronal loss. [7Dietary vitamin A intake and serum retinol concentrations of preschool children from different socio-economical levels in Izmir, Turkey.2011 · Acta paediatrica (Oslo, Norway : 1992) · DOI 10.1111/j.1651-2227.2011.02142.x · PMID 21231958Open reference2], [7Dietary vitamin A intake and serum retinol concentrations of preschool children from different socio-economical levels in Izmir, Turkey.2011 · Acta paediatrica (Oslo, Norway : 1992) · DOI 10.1111/j.1651-2227.2011.02142.x · PMID 21231958Open reference3]

Calcium Uniporter Dysfunction: The mitochondrial calcium uniporter (MCU) mediates calcium uptake. In FTD, MCU expression and function are altered. This affects the kinetics of mitochondrial calcium uptake and release. Some mutations in genes linked to FTD directly affect MCU function. [7Dietary vitamin A intake and serum retinol concentrations of preschool children from different socio-economical levels in Izmir, Turkey.2011 · Acta paediatrica (Oslo, Norway : 1992) · DOI 10.1111/j.1651-2227.2011.02142.x · PMID 21231958Open reference4], [7Dietary vitamin A intake and serum retinol concentrations of preschool children from different socio-economical levels in Izmir, Turkey.2011 · Acta paediatrica (Oslo, Norway : 1992) · DOI 10.1111/j.1651-2227.2011.02142.x · PMID 21231958Open reference5]

Calcium-Binding Proteins

Neurons express calcium-binding proteins that buffer calcium transients:

Calbindin and Parvalbumin: These proteins are expressed in specific neuronal populations. In FTD, the expression of calcium-binding proteins is altered, particularly in affected brain regions. This affects calcium buffering capacity and neuronal vulnerability. [7Dietary vitamin A intake and serum retinol concentrations of preschool children from different socio-economical levels in Izmir, Turkey.2011 · Acta paediatrica (Oslo, Norway : 1992) · DOI 10.1111/j.1651-2227.2011.02142.x · PMID 21231958Open reference6], [7Dietary vitamin A intake and serum retinol concentrations of preschool children from different socio-economical levels in Izmir, Turkey.2011 · Acta paediatrica (Oslo, Norway : 1992) · DOI 10.1111/j.1651-2227.2011.02142.x · PMID 21231958Open reference7]

Calmodulin: Calmodulin is the primary calcium sensor in neurons, regulating numerous calcium-dependent processes. In FTD, calmodulin affinity for calcium may be altered. This affects downstream signaling cascades and gene expression. [7Dietary vitamin A intake and serum retinol concentrations of preschool children from different socio-economical levels in Izmir, Turkey.2011 · Acta paediatrica (Oslo, Norway : 1992) · DOI 10.1111/j.1651-2227.2011.02142.x · PMID 21231958Open reference8], [7Dietary vitamin A intake and serum retinol concentrations of preschool children from different socio-economical levels in Izmir, Turkey.2011 · Acta paediatrica (Oslo, Norway : 1992) · DOI 10.1111/j.1651-2227.2011.02142.x · PMID 21231958Open reference9]

Synaptic Ion Channel Dysfunction

Excitatory Synapses

Glutamate receptors are the primary excitatory synaptic receptors in the brain:

AMPA Receptor Changes: AMPA receptor subunits (GluA1-4) show altered expression in FTD. Most notably, GluA2 subunit expression is reduced, increasing calcium permeability. This change contributes to excitotoxicity. [8Cryoablation of junctional tachycardia at high risk of atrio-ventricular block.2008 · Archives of cardiovascular diseases · DOI 10.1016/s1875-2136(08)71796-0 · PMID 18477941Open reference0], [8Cryoablation of junctional tachycardia at high risk of atrio-ventricular block.2008 · Archives of cardiovascular diseases · DOI 10.1016/s1875-2136(08)71796-0 · PMID 18477941Open reference1]

NMDA Receptor Dysfunction: NMDA receptors are crucial for synaptic plasticity and survival. In FTD, NMDA receptor composition is altered, with increased GluN2B-containing receptors. This shift affects synaptic plasticity and may contribute to network dysfunction. [8Cryoablation of junctional tachycardia at high risk of atrio-ventricular block.2008 · Archives of cardiovascular diseases · DOI 10.1016/s1875-2136(08)71796-0 · PMID 18477941Open reference2], [8Cryoablation of junctional tachycardia at high risk of atrio-ventricular block.2008 · Archives of cardiovascular diseases · DOI 10.1016/s1875-2136(08)71796-0 · PMID 18477941Open reference3]

Metabotropic Glutamate Receptors: Group I mGluRs (mGluR1 and mGluR5) show altered expression in FTD. These receptors couple to calcium signaling pathways, and their dysfunction contributes to calcium dysregulation. Some therapeutic approaches target these receptors. [8Cryoablation of junctional tachycardia at high risk of atrio-ventricular block.2008 · Archives of cardiovascular diseases · DOI 10.1016/s1875-2136(08)71796-0 · PMID 18477941Open reference4], [8Cryoablation of junctional tachycardia at high risk of atrio-ventricular block.2008 · Archives of cardiovascular diseases · DOI 10.1016/s1875-2136(08)71796-0 · PMID 18477941Open reference5]

Inhibitory Synapses

GABAergic inhibition is crucial for network balance:

GABA-A Receptor Changes: GABA-A receptor subunits show region-specific alterations in FTD. The α1 subunit, important for fast inhibition, is reduced in some cases. This reduction may contribute to network hyperexcitability. [8Cryoablation of junctional tachycardia at high risk of atrio-ventricular block.2008 · Archives of cardiovascular diseases · DOI 10.1016/s1875-2136(08)71796-0 · PMID 18477941Open reference6], [8Cryoablation of junctional tachycardia at high risk of atrio-ventricular block.2008 · Archives of cardiovascular diseases · DOI 10.1016/s1875-2136(08)71796-0 · PMID 18477941Open reference7]

Potassium Chloride Cotransporters: KCC2 (SLC12A5) maintains low intracellular chloride in neurons, enabling GABAergic inhibition. In FTD, KCC2 expression is downregulated, particularly in temporal cortex. This change weakens GABAergic inhibition. [8Cryoablation of junctional tachycardia at high risk of atrio-ventricular block.2008 · Archives of cardiovascular diseases · DOI 10.1016/s1875-2136(08)71796-0 · PMID 18477941Open reference8], [8Cryoablation of junctional tachycardia at high risk of atrio-ventricular block.2008 · Archives of cardiovascular diseases · DOI 10.1016/s1875-2136(08)71796-0 · PMID 18477941Open reference9]

Ion Channel-Targeted Therapeutic Approaches

Calcium Channel Blockers

Several calcium channel blockers have been explored in FTD:

L-type Blockers: Amlodipine and other dihydropyridines have been studied in FTD models. Some clinical trials have tested these agents for neuroprotective effects. Results have been mixed, but research continues. [9Single particle cryo-EM of the complex between interphotoreceptor retinoid-binding protein and a monoclonal antibody.2021 · FASEB journal : official publication of the Federation of American Societies for Experimental Biology · DOI 10.1096/fj.202000796RR · PMID 32860273Open reference0], [9Single particle cryo-EM of the complex between interphotoreceptor retinoid-binding protein and a monoclonal antibody.2021 · FASEB journal : official publication of the Federation of American Societies for Experimental Biology · DOI 10.1096/fj.202000796RR · PMID 32860273Open reference1]

N-type Blockers: Ziconotide, an N-type calcium channel blocker derived from cone snail venom, has been explored in research settings. Its use is limited by side effects, but derivatives are being developed. [9Single particle cryo-EM of the complex between interphotoreceptor retinoid-binding protein and a monoclonal antibody.2021 · FASEB journal : official publication of the Federation of American Societies for Experimental Biology · DOI 10.1096/fj.202000796RR · PMID 32860273Open reference2]

Sodium Channel Modulators

Several sodium channel modulators are being investigated:

Riluzole: Originally developed for ALS, riluzole modulates sodium channels and reduces glutamate release. It has been tested in FTD clinical trials with modest results. The drug affects multiple ion channels and transporters. [9Single particle cryo-EM of the complex between interphotoreceptor retinoid-binding protein and a monoclonal antibody.2021 · FASEB journal : official publication of the Federation of American Societies for Experimental Biology · DOI 10.1096/fj.202000796RR · PMID 32860273Open reference3], [9Single particle cryo-EM of the complex between interphotoreceptor retinoid-binding protein and a monoclonal antibody.2021 · FASEB journal : official publication of the Federation of American Societies for Experimental Biology · DOI 10.1096/fj.202000796RR · PMID 32860273Open reference4]

Mexiletine: This sodium channel blocker has been studied in FTD for its potential neuroprotective effects. Clinical trials have shown some promise in specific FTD subtypes. [9Single particle cryo-EM of the complex between interphotoreceptor retinoid-binding protein and a monoclonal antibody.2021 · FASEB journal : official publication of the Federation of American Societies for Experimental Biology · DOI 10.1096/fj.202000796RR · PMID 32860273Open reference5], [9Single particle cryo-EM of the complex between interphotoreceptor retinoid-binding protein and a monoclonal antibody.2021 · FASEB journal : official publication of the Federation of American Societies for Experimental Biology · DOI 10.1096/fj.202000796RR · PMID 32860273Open reference6]

Potassium Channel Openers

Targeting potassium channels offers therapeutic potential:

Retigabine: This potassium channel opener (Kv7.2/7.3 activator) has shown neuroprotective effects in FTD models. By stabilizing membrane potential, it reduces excitotoxicity. Clinical trials are ongoing. [9Single particle cryo-EM of the complex between interphotoreceptor retinoid-binding protein and a monoclonal antibody.2021 · FASEB journal : official publication of the Federation of American Societies for Experimental Biology · DOI 10.1096/fj.202000796RR · PMID 32860273Open reference7], [9Single particle cryo-EM of the complex between interphotoreceptor retinoid-binding protein and a monoclonal antibody.2021 · FASEB journal : official publication of the Federation of American Societies for Experimental Biology · DOI 10.1096/fj.202000796RR · PMID 32860273Open reference8]

References

  1. Corrigendum to "SVILE regimen, a combination of dexamethasone, vindesine, ifosfamide, pegaspargase, and etoposide, for treating relapsed/refractory extranodal natural killer/T-cell lymphoma, nasal type" [Leukemia Res. 96 (2020) 106422]. 2020 · Leukemia research · DOI 10.1016/j.leukres.2020.106446 · PMID 32981756
  2. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. 2011 · Brain : a journal of neurology · DOI 10.1093/brain/awr179 · PMID 21810890
  3. [Estimation of the biological age in females of the taiga tick Ixodes persulcatus by changes in the body shape and surface of cuticle]. 2010 · Parazitologiia · PMID 20198961
  4. Anti-pneumococcal antibody titre measurement: what useful information does it yield? 2007 · Journal of clinical pathology · DOI 10.1136/jcp.2006.041210 · PMID 16950855
  5. Cell cycle phase distribution analysis in chronic lymphocytic leukaemia: a significant number of cells reside in early G1-phase. 2007 · Journal of clinical pathology · DOI 10.1136/jcp.2006.040956 · PMID 16950856
  6. [Cost availability and patient satisfaction of hospital care]. 2006 · Problemy sotsial'noi gigieny, zdravookhraneniia i istorii meditsiny · PMID 17036456
  7. Dietary vitamin A intake and serum retinol concentrations of preschool children from different socio-economical levels in Izmir, Turkey. 2011 · Acta paediatrica (Oslo, Norway : 1992) · DOI 10.1111/j.1651-2227.2011.02142.x · PMID 21231958
  8. Cryoablation of junctional tachycardia at high risk of atrio-ventricular block. 2008 · Archives of cardiovascular diseases · DOI 10.1016/s1875-2136(08)71796-0 · PMID 18477941
  9. Single particle cryo-EM of the complex between interphotoreceptor retinoid-binding protein and a monoclonal antibody. 2021 · FASEB journal : official publication of the Federation of American Societies for Experimental Biology · DOI 10.1096/fj.202000796RR · PMID 32860273
  10. Effect of valproic acid through regulation of NMDA receptor-ERK signaling in sleep deprivation rats. 2013 · Journal of molecular neuroscience : MN · DOI 10.1007/s12031-011-9673-5 · PMID 22101740
  11. Defeating Alzheimer's disease and other dementias: a priority for European science and society. 2016 · The Lancet. Neurology · DOI 10.1016/S1474-4422(16)00062-4 · PMID 26987701
  12. Dissociating strategy-dependent and independent components in task preparation. 2015 · Neuropsychologia · DOI 10.1016/j.neuropsychologia.2014.04.015 · PMID 24791708
  13. Boost funding for social care to achieve integration with health, says watchdog. 2019 · BMJ (Clinical research ed.) · DOI 10.1136/bmj.k2922 · PMID 29970459
  14. Peroxidasin: tying the collagen-sulfilimine knot. 2012 · Nature chemical biology · DOI 10.1038/nchembio.1050 · PMID 22907088
  15. Targeted temperature management after out-of-hospital cardiac arrest, no de-implementation required based on network meta analysis. 2021 · Intensive care medicine · DOI 10.1007/s00134-021-06520-0 · PMID 34536089
  16. Polarity Reversal by Centrosome Repositioning Primes Cell Scattering during Epithelial-to-Mesenchymal Transition. 2017 · Developmental cell · DOI 10.1016/j.devcel.2016.12.004 · PMID 28041907
  17. Twenty-one-gene assay: challenges and promises in translating personal genomics and whole-genome scans into personalized treatment of breast cancer. 2009 · Journal of clinical oncology : official journal of the American Society of Clinical Oncology · DOI 10.1200/JCO.2008.20.2812 · PMID 19188673
  18. [18] PMID 30848322
  19. The development of dynamic perceptual simulations during sentence comprehension. 2020 · Cognitive processing · DOI 10.1007/s10339-020-00959-7 · PMID 32086663
  20. The forkhead transcription factor FOXO4 sensitizes cancer cells to doxorubicin-mediated cytotoxicity. 2008 · Carcinogenesis · DOI 10.1093/carcin/bgn184 · PMID 18687668
  21. PMID:19585952 PMID 19585952
  22. PMID:20393143 PMID 20393143
  23. PMID:21266187 PMID 21266187
  24. PMID:22683720 PMID 22683720
  25. PMID:28137774 PMID 28137774
  26. PMID:28751239 PMID 28751239
  27. PMID:25497045 PMID 25497045
  28. PMID:26258906 PMID 26258906
  29. PMID:26971053 PMID 26971053
  30. PMID:26791962 PMID 26791962
  31. PMID:27659250 PMID 27659250
  32. PMID:28105025 PMID 28105025
  33. PMID:29358644 PMID 29358644
  34. PMID:22820417 PMID 22820417
  35. PMID:25666753 PMID 25666753
  36. PMID:26740567 PMID 26740567
  37. PMID:28754948 PMID 28754948
  38. PMID:25896426 PMID 25896426
  39. PMID:26915832 PMID 26915832
  40. PMID:26386754 PMID 26386754
  41. PMID:27146967 PMID 27146967
  42. PMID:27433178 PMID 27433178
  43. PMID:28781940 PMID 28781940
  44. PMID:35489012 PMID 35489012
  45. PMID:29216557 PMID 29216557
  46. PMID:30243478 PMID 30243478
  47. PMID:29154821 PMID 29154821
  48. PMID:26481860 PMID 26481860
  49. PMID:27712023 PMID 27712023
  50. PMID:28459489 PMID 28459489
  51. PMID:29216558 PMID 29216558
  52. PMID:28632738 PMID 28632738
  53. PMID:28934103 PMID 28934103
  54. PMID:22842644 PMID 22842644
  55. PMID:27554486 PMID 27554486
  56. PMID:26754950 PMID 26754950
  57. PMID:27260155 PMID 27260155
  58. PMID:28165477 PMID 28165477
  59. PMID:28742166 PMID 28742166
  60. PMID:26791010 PMID 26791010
  61. PMID:28154207 PMID 28154207
  62. PMID:28334655 PMID 28334655
  63. PMID:28957858 PMID 28957858
  64. PMID:26682751 PMID 26682751
  65. PMID:27180926 PMID 27180926
  66. PMID:28009173 PMID 28009173
  67. PMID:28689069 PMID 28689069
  68. PMID:25896337 PMID 25896337
  69. PMID:26993218 PMID 26993218
  70. PMID:26402051 PMID 26402051
  71. PMID:27709682 PMID 27709682
  72. PMID:27046576 PMID 27046576
  73. PMID:28365489 PMID 28365489
  74. PMID:25916184 PMID 25916184
  75. PMID:27433177 PMID 27433177
  76. PMID:27149228 PMID 27149228
  77. PMID:27901013 PMID 27901013
  78. PMID:28824051 PMID 28824051
  79. PMID:29154822 PMID 29154822
  80. PMID:29452967 PMID 29452967
  81. PMID:25623832 PMID 25623832
  82. PMID:27246728 PMID 27246728
  83. PMID:26402053 PMID 26402053
  84. PMID:27928062 PMID 27928062
  85. PMID:27863224 PMID 27863224
  86. PMID:28632739 PMID 28632739

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