Affinage

GDAP1

Ganglioside-induced differentiation-associated protein 1 · UniProt Q8TB36

Length
358 aa
Mass
41.3 kDa
Annotated
2026-06-10
100 papers in source corpus 27 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GDAP1 is a tail-anchored outer mitochondrial membrane protein that functions as a fission factor coupling mitochondrial dynamics to redox state, calcium handling, and interorganelle communication in neurons (PMID:19782751, PMID:19340293). It anchors in the mitochondrial outer membrane through a single transmembrane domain flanked by basic residues and peripheral helices, and these targeting determinants are required for its pro-fission activity (PMID:19340293, PMID:37778197). GDAP1 drives mitochondrial fission in a manner dependent on Drp1 and Fis1, and additionally localizes to peroxisomes via Pex19 to promote Drp1/Mff-dependent peroxisomal fission, with its hydrophobic domain 1 (HD1) essential for both activities (PMID:19782751, PMID:23628762). Although GDAP1 adopts a GST-like fold, structural and biochemical work shows it has lost canonical glutathione binding through alterations in G-site residues while retaining H-site substrate binding; HD1 acts as an autoinhibitory switch between fission-active and inactive conformations (PMID:27841286, PMID:32274853, PMID:33585569). Functionally, GDAP1 raises cellular glutathione and mitochondrial membrane potential, supports store-operated Ca2+ entry (SOCE) and SOCE-stimulated mitochondrial respiration, and organizes membrane contact sites between mitochondria and the ER, lysosomes, and peroxisomes—acting as a LAMP-1 tether for mitochondria-lysosome contacts and a tether for mitochondria-peroxisome contacts (PMID:21965300, PMID:23542510, PMID:28220846, PMID:33372681, PMID:39801517). It links the actin/microtubule cytoskeleton to mitochondrial fission through redox-dependent interactions with Cofilin-1 and β-tubulin that govern DRP1 recruitment, while also sustaining pyruvate dehydrogenase complex activity and bioenergetic flexibility (PMID:21890626, PMID:35662277). GDAP1 expression is transcriptionally activated by YY1 (PMID:19720140). Loss of GDAP1 in mice, iPSC-derived motor neurons, and Drosophila produces enlarged or abnormal mitochondria, impaired axonal mitochondrial transport, bioenergetic and Ca2+ homeostasis defects, and progressive motor and sensory neuron degeneration; recessive mutations impair fission, glutathione elevation, and contact-site formation, whereas dominant mutations disrupt fusion, increase ROS, and alter mitochondria-lysosome contact dynamics, together underlying Charcot-Marie-Tooth neuropathy (PMID:21965300, PMID:24480485, PMID:25860513, PMID:33582224, PMID:25168384, PMID:37393339).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 2005 High

    Established where GDAP1 acts by showing it is a mitochondrial protein whose C-terminal transmembrane domains determine its localization, anchoring all subsequent mechanism to mitochondria.

    Evidence Overexpression with organelle co-localization, subcellular fractionation, and C-terminal deletion in neuroblastoma and COS-7 cells

    PMID:15772096

    Open questions at the time
    • Did not define molecular function
    • Membrane topology and anchoring mode unresolved
  2. 2009 High

    Defined GDAP1's core molecular activity as a Drp1/Fis1-dependent fission factor and distinguished recessive (loss of fission) from dominant (impaired fusion, increased ROS) mutation mechanisms.

    Evidence Overexpression/knockdown, morphology, ROS and apoptosis assays, and dominant-negative epistasis with Drp1 and Fis1 in cell lines

    PMID:19782751

    Open questions at the time
    • Direct biochemical mechanism of fission not shown
    • How GDAP1 engages the fission machinery undefined
  3. 2009 High

    Resolved the membrane anchoring requirement by showing GDAP1 is a tail-anchored MOM protein whose TMD plus flanking basic residues are required for both targeting and fission.

    Evidence TMD and flanking-residue mutagenesis with targeting and fission readouts in cell lines

    PMID:19340293

    Open questions at the time
    • Insertion machinery not identified
    • Did not address peripheral helix contributions
  4. 2009 Medium

    Identified the upstream transcriptional control of GDAP1, showing YY1 directly activates its promoter.

    Evidence EMSA, luciferase reporter, and YY1 overexpression/RNAi with endogenous mRNA measurement

    PMID:19720140

    Open questions at the time
    • Physiological/neuronal context of YY1 regulation unclear
    • Other regulators not mapped
  5. 2011 High

    Linked GDAP1 fission to glutathione and redox homeostasis, connecting morphology to oxidative protection.

    Evidence Overexpression/RNAi in HT22 and NSC34 cells, GSH and membrane potential assays, and CMT4A patient fibroblasts

    PMID:21965300

    Open questions at the time
    • Mechanism by which GDAP1 raises GSH not established
    • Whether direct enzymatic activity is involved unresolved at this stage
  6. 2011 Medium

    Connected GDAP1 to the cytoskeleton and a conserved fission-microtubule axis through functional relatedness to Fis1 and physical β-tubulin interaction.

    Evidence Yeast fis1Δ complementation, cell cycle analysis, and Co-IP of GDAP1 with TUBB

    PMID:21890626

    Open questions at the time
    • Functional consequence of β-tubulin binding not demonstrated in this study
    • Yeast surrogate may not reflect neuronal context
  7. 2013 High

    Extended GDAP1's fission role to peroxisomes via Pex19 import and showed differential mutation sensitivity between mitochondrial and peroxisomal fission.

    Evidence Peroxisomal co-localization, Pex19 interaction, knockdown/rescue, and Drp1/Mff epistasis with HD1 mutagenesis

    PMID:23628762

    Open questions at the time
    • Why N-terminal mutations preferentially impair mitochondrial fission unexplained
  8. 2013 High

    Placed GDAP1 at mitochondria-ER contacts and in calcium signaling by linking it to RAB6B/caytaxin, SOCE, and mitochondrial positioning.

    Evidence Co-IP of RAB6B and caytaxin, siRNA knockdown, live-cell Ca2+ imaging and SOCE measurement in SH-SY5Y cells

    PMID:23542510

    Open questions at the time
    • Direct tethering molecules at ER contacts not identified here
    • Causal chain from contacts to SOCE incomplete
  9. 2014 High

    Demonstrated in vivo consequences of GDAP1 loss—enlarged mitochondria, impaired axonal transport, Schwann-cell-autonomous neuropathy—and identified GDAP1L1 as a redox-triggered compensatory paralog.

    Evidence Gdap1 knockout mouse, live transport imaging, Schwann-cell-specific ablation, mtDNA quantification, GDAP1L1 translocation assays

    PMID:24480485

    Open questions at the time
    • Molecular trigger for GDAP1L1 translocation undefined
    • Mechanism of transport defect not resolved
  10. 2014 High

    Connected GDAP1 loss to motor neuron bioenergetic failure and Ca2+ dysregulation, tying organelle defects to functional decline.

    Evidence Gdap1 KO motor neurons with EM, Ca2+ imaging, SOCE assays, respirometry and histopathology

    PMID:25860513 PMID:33582224

    Open questions at the time
    • Primary lesion versus secondary consequence not fully separated
    • Cell-type selectivity of degeneration unexplained
  11. 2014 Medium

    Identified JPH1 as a functional partner restoring SOCE in GDAP1-deficient cells and showed dominant mutant retains JPH1 at mitochondria.

    Evidence JPH1 rescue of SOCE, STIM1 co-localization, and dominant p.R120W mutant expression

    PMID:25168384

    Open questions at the time
    • Direct GDAP1-JPH1 physical interaction not shown
    • Single-lab functional model
  12. 2014 Medium

    Confirmed conserved organismal function via Drosophila ortholog and established that oxidative stress is a consequence rather than primary cause of mitochondrial dysfunction.

    Evidence Tissue-specific Drosophila Gdap1 overexpression/RNAi with morphology, metabolic and degeneration readouts

    PMID:25122658

    Open questions at the time
    • Molecular ordering of dysfunction vs ROS not biochemically dissected
  13. 2016 High

    Provided the first enzymatic and conformational model: GDAP1 has theta-class-like GST activity gated by an autoinhibitory HD1 acting as a fission/enzyme molecular switch.

    Evidence Recombinant GST activity assay, HD1 mutagenesis, and cellular fission assay

    PMID:27841286

    Open questions at the time
    • Physiological substrate not identified
    • Switch reconciliation with later loss-of-GSH-binding data needed
  14. 2017 High

    Linked GDAP1 calcium function directly to bioenergetics, showing recessive α-loop mutations blunt SOCE-stimulated respiration via mitochondrial Ca2+ uptake.

    Evidence Knockdown, CMT mutant expression, SOCE, Seahorse respirometry, MCU silencing epistasis and ER-Ca2+ measurement

    PMID:28220846

    Open questions at the time
    • How GDAP1 controls SOCE molecularly remains open
    • Dominant-versus-recessive divergence mechanism unresolved
  15. 2020 High

    Revised the enzymatic model by demonstrating GDAP1 has lost glutathione binding while retaining H-site substrate binding, and that morphology effects depend on its unique hydrophobic domain.

    Evidence Recombinant glutathione binding assay, structural analysis, α-loop mutagenesis and overexpression morphology assay

    PMID:32274853

    Open questions at the time
    • True physiological substrate of the retained H-site unknown
    • Reconciling residual catalytic activity with no GSH binding
  16. 2021 High

    Provided the crystal structure revealing a GDAP1-specific dimerization mode, catalytic inactivity toward classical GST substrates, and a CMT-cluster-adjacent fatty acid binding pocket.

    Evidence X-ray crystallography, metabolite screening, GST assay, thermal stability and analytical ultracentrifugation

    PMID:33585569

    Open questions at the time
    • Functional role of fatty acid ligand in cells unknown
    • Significance of oligomerization for fission untested
  17. 2021 High

    Defined GDAP1 as a mitochondria-lysosome tether (with LAMP-1 and PIKfyve) and placed it in basal autophagy and lysosome reformation.

    Evidence Reciprocal Co-IP of LAMP-1 and PIKfyve, knockdown, MCS and lysosome imaging, TFEB activation and GSH rescue in neuronal cells

    PMID:33372681

    Open questions at the time
    • Direct tethering geometry not structurally defined
    • GSH-independent contact-site defects mechanism unclear
  18. 2021 Medium

    Showed GDAP1 clinical variants differentially remodel mitochondria-lysosome contacts and lysosome-to-mitochondria Ca2+ transfer, distinguishing dominant from recessive effects.

    Evidence Clinical variant expression with live-cell MCS imaging and morphology assays

    PMID:36912213

    Open questions at the time
    • Only two variants tested
    • Causal link to neuropathy phenotype not established
  19. 2022 High

    Mechanistically connected GDAP1 to cytoskeletal control of DRP1 recruitment and to mitochondrial metabolism via redox-dependent Cofilin-1/β-tubulin interactions and PDC regulation.

    Evidence Co-IP of Cofilin-1 and β-tubulin, knockdown in SH-SY5Y, patient-derived motoneurons, F-actin/DRP1/PDC and metabolic assays

    PMID:35662277

    Open questions at the time
    • Redox signal that gates the interactions not identified
    • Direct versus indirect PDC regulation unresolved
  20. 2023 Medium

    Provided a biophysical membrane-assembly model with a single transmembrane helix and two leaflet-interacting peripheral helices.

    Evidence Synchrotron OCD spectroscopy and SAXS on peptides and full-length protein in lipid systems

    PMID:37778197

    Open questions at the time
    • No functional mutagenesis validation of the model
    • Topology in native mitochondria not confirmed
  21. 2023 High

    Showed CMT mutations across helices α3/α6/α7 cause destabilization without gross structural change, identifying protein stability loss as a shared disease mechanism.

    Evidence Crystal structures of R120Q, A247V, R282H, DSF stability assays, SAXS and conservation analysis of multiple variants

    PMID:37058526

    Open questions at the time
    • How destabilization translates to functional loss in cells not shown
  22. 2023 Medium

    Defined a redox-inflammatory degeneration axis in GDAP1-null motor neurons linking mitochondrial fragmentation, mitophagy, metabolic remodeling, ROS and p38 MAPK activation.

    Evidence Gdap1 KO iPSC-derived motor neurons with morphology, autophagy/mitophagy markers, proteomics, ROS, membrane potential, p38 and transcriptomics

    PMID:37393339

    Open questions at the time
    • Causal ordering of redox versus inflammatory events unresolved
    • Single-lab iPSC model
  23. 2024 Medium

    Identified GDAP1 as a mitochondria-peroxisome contact tether whose loss causes peroxisomal abnormalities reversible by PPARγ activation or glutathione supplementation.

    Evidence High-resolution and live-cell MCS imaging in Gdap1-/- mice and patient fibroblasts, omics, and pharmacological rescue (preprint)

    PMID:39801517

    Open questions at the time
    • Preprint, not peer-reviewed
    • Direct peroxisomal tethering partner not identified
  24. 2025 Medium

    Showed BNIP3-driven mitophagy partially compensates for GDAP1 loss, defining a protective response axis.

    Evidence GDAP1 knockdown with mitochondrial proteomics and Drosophila BNIP3 epistasis with behavioral assays

    PMID:40618856

    Open questions at the time
    • Mechanism linking GDAP1 loss to BNIP3 induction unknown
    • Therapeutic relevance untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The physiological substrate of the retained GST-like H-site and the precise molecular mechanism by which GDAP1 nucleates fission and tethers multiple organelles remain unresolved.
  • No native substrate identified
  • No reconstituted fission/tethering mechanism
  • Dominant-vs-recessive structural basis incompletely defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 3 GO:0060090 molecular adaptor activity 3 GO:0008092 cytoskeletal protein binding 2 GO:0008289 lipid binding 1
Localization
GO:0005739 mitochondrion 3 GO:0005764 lysosome 2 GO:0005777 peroxisome 2 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-1643685 Disease 3 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-9612973 Autophagy 3 R-HSA-8953897 Cellular responses to stimuli 2
Partners
CFL1DRP1FIS1LAMP1MFFPEX19RAB6BTUBB

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 GDAP1 protein localizes to mitochondria, and its C-terminal transmembrane domains are necessary for correct mitochondrial localization. Missense mutations do not alter the mitochondrial localization pattern of the wild-type protein. Transient overexpression in human neuroblastoma and COS-7 cells with co-localization using organelle markers; western blot analysis of subcellular fractions with anti-GDAP1 polyclonal antibodies; C-terminal domain deletion experiments Human molecular genetics High 15772096
2009 GDAP1 is a mitochondrial fission factor whose fission activity depends on Drp1 and Fis1. Overexpression or knockdown of wild-type GDAP1 does not influence susceptibility to apoptosis. Recessively inherited CMT mutations reduce fission activity, while dominantly inherited mutations interfere with mitochondrial fusion and increase ROS production, uneven mitochondrial transmembrane potentials, and susceptibility to apoptosis. Overexpression and knockdown experiments in cell lines; mitochondrial morphology assays; ROS measurement; apoptosis susceptibility assays; dominant-negative analysis with Drp1 and Fis1 mutants Neurobiology of disease High 19782751
2009 GDAP1 is a tail-anchored mitochondrial outer membrane (MOM) protein. It contains a single transmembrane domain (TMD) that, together with adjacent basic amino acids, is critical for MOM targeting. The basic amino acids bordering the TMD on the cytoplasmic side are required for both MOM targeting and GDAP1-mediated fission. TMD sequence, length, and hydrophobicity per se do not influence fission function if MOM targeting is maintained. Mutagenesis of TMD and flanking basic residues combined with mitochondrial targeting assays and mitochondrial fission functional readouts in cell lines PloS one High 19340293
2011 Wild-type GDAP1 overexpression increases total cellular glutathione (GSH) content and mitochondrial membrane potential. GDAP1 knockdown increases susceptibility to GSH depletion-mediated oxidative stress. Fibroblasts from CMT4A patients had reduced GDAP1 levels, reduced GSH, and reduced mitochondrial membrane potential. Recessively inherited CMT mutations that reduce fission activity fail to increase GSH or mitochondrial membrane potential. Overexpression and RNAi knockdown in HT22 and NSC34 neuronal cell lines; GSH measurement assay; mitochondrial membrane potential measurement; patient-derived fibroblast analysis Human molecular genetics High 21965300
2013 GDAP1 is also targeted to peroxisomes via the import receptor Pex19. GDAP1 knockdown causes peroxisomal elongation rescuable by re-expressing GDAP1 or CMT missense mutants. Peroxisomal fission by GDAP1 depends on the integrity of its hydrophobic domain 1 (HD1) and on Drp1 and Mff, as does mitochondrial fission. CMT mutations in the N-terminal GDAP1 domains more critically impair mitochondrial fission than peroxisomal fission. Immunofluorescence co-localization with peroxisomal markers; Pex19 interaction assay; knockdown and rescue experiments; dominant-negative Drp1 and Mff RNAi epistasis; HD1 mutagenesis EMBO reports High 23628762
2013 GDAP1 interacts with the vesicle-organelle trafficking proteins RAB6B and caytaxin. GDAP1 silencing in SH-SY5Y cells causes abnormal mitochondrial distribution, reduces mitochondria-ER contact sites, and impairs mitochondrial mobilization toward the plasma membrane upon ER-Ca2+ depletion. GDAP1 silencing reduces Ca2+ inflow through store-operated Ca2+ entry (SOCE) and SOCE-driven mitochondrial Ca2+ uptake, without affecting mitochondrial Ca2+ uptake per se, ER-Ca2+ levels, or Ca2+ flow from ER to mitochondria. Co-immunoprecipitation of RAB6B and caytaxin; siRNA knockdown; live-cell Ca2+ imaging; mitochondrial distribution assays; SOCE measurement Neurobiology of disease High 23542510
2014 In Gdap1 knockout mice, intra-axonal mitochondria are larger and mitochondrial transport is impaired in cultured sensory neurons. Ablation of Gdap1 in Schwann cells recapitulates the hypomyelinating neuropathy phenotype. Mitochondrial DNA biogenesis and content are increased in the peripheral nervous system but not CNS of Gdap1-/- mice. The GDAP1 paralogue GDAP1L1, mainly expressed in the CNS, translocates from cytosol to mitochondria in response to elevated oxidized glutathione, and this translocation is necessary to compensate for GDAP1 loss. Gdap1 knockout mouse model; live mitochondrial transport imaging in cultured sensory neurons; Schwann cell-specific Gdap1 ablation; mitochondrial DNA content quantification; GDAP1L1 localization experiments with oxidized glutathione treatment Brain : a journal of neurology High 24480485
2014 Gdap1 knockout mouse motor neurons show large and defective mitochondria, ER cisternae changes, reduced α-tubulin acetylation, increased autophagy vesicles, reduced cytosolic calcium, and reduced SOCE response. These changes are associated with progressive loss of motor neurons and neuromuscular junction defects. Gdap1 knockout mouse; embryonic motor neuron cultures; electron microscopy; live-cell Ca2+ imaging; SOCE assays; histopathology PLoS genetics High 25860513
2011 GDAP1 and human FIS1 are functionally related: GDAP1 complements the G2/M cell cycle delay in S. cerevisiae fis1Δ cells. CMT missense mutations rescue other fis1Δ phenotypes but not the cell cycle delay. GDAP1 physically interacts with β-tubulin (TUBB), and yeast Fis1p interacts with yeast β-tubulin Tub2p, suggesting a conserved interaction between the mitochondrial fission machinery and microtubules. Yeast complementation assay; cell cycle analysis; Co-immunoprecipitation of GDAP1 with TUBB; CMT mutant rescue experiments The Journal of biological chemistry Medium 21890626
2016 GDAP1 possesses theta-class-like glutathione S-transferase (GST) enzymatic activity demonstrated with recombinant protein. This GST activity is regulated in an autoinhibitory manner by the C-terminal hydrophobic domain 1 (HD1). The amphipathic pattern of HD1 is required for GDAP1 to induce membrane dynamics (fission). Both fission and GST activities critically depend on HD1, suggesting a molecular switch between pro-fission active and autoinhibited inactive conformations. Recombinant GDAP1 protein GST activity assay; HD1 domain mutagenesis; mitochondrial fission assay; in vitro biochemistry Scientific reports High 27841286
2017 CMT recessive loss-of-function mutations in the α-loop of GDAP1 reduce SOCE and SOCE-stimulated mitochondrial respiration in neuroblastoma cells, while dominant mutations do not. GDAP1 silencing or MCU silencing/mitochondrial depolarization (which prevent mitochondrial Ca2+ uptake) both blunt Ca2+-dependent upregulation of respiration after SOCE. Reduced ER-Ca2+ levels are also observed in cells with recessive GDAP1 mutations. GDAP1 knockdown; CMT mutant expression; SOCE measurement; Seahorse respirometry; MCU silencing epistasis; ER-Ca2+ measurement Scientific reports High 28220846
2021 GDAP1 participates in basal autophagy and its depletion affects LC3 and PI3P biology in autophagosome biogenesis and membrane trafficking from MAMs. GDAP1 interacts with PIKfyve kinase (a pH-dependent lysosomal regulator) and with LAMP-1, establishing GDAP1-LAMP-1 as a new tethering pair for mitochondria-lysosome membrane contact sites (MCSs). GDAP1 deficiency reduces mitochondria-lysosome MCSs, causes giant lysosomes with hydrolytic activity, delays autophagic lysosome reformation, and activates TFEB. GSH supplementation rescues lysosome membrane defects and mitochondrial network abnormalities but not interorganelle MCSs or early autophagic events. Co-immunoprecipitation of GDAP1 with LAMP-1 and PIKfyve; siRNA knockdown; live-cell imaging of MCSs; lysosome size/hydrolytic activity assays; TFEB activation assay; GSH rescue experiments in neuronal cells Human molecular genetics High 33372681
2022 GDAP1 interacts with the actin-depolymerizing protein Cofilin-1 and with β-tubulin in a redox-dependent manner. GDAP1 loss reduces F-actin near mitochondria, restricts mitochondrial localization of the fission factor DRP1, and causes mitochondrial tubularity. GDAP1 silencing also disrupts mitochondria-ER contact sites, lowers mitochondrial Ca2+ levels, and inhibits the pyruvate dehydrogenase complex (PDC), causing glutamine dependence and reduced cytosolic lipid droplets. Co-immunoprecipitation of GDAP1 with Cofilin-1 and β-tubulin; siRNA knockdown in SH-SY5Y; patient-derived motoneurons; phalloidin F-actin staining; DRP1 localization assay; Seahorse metabolic assay; PDC activity measurement; mitochondria-ER contact site imaging Communications biology High 35662277
2020 GDAP1 has lost the ability to bind glutathione despite retaining substrate binding activity in its H-site. The α-loop within the H-site motif is the primary determinant for substrate binding. Critical G-site residues that canonically interact with glutathione are altered in GDAP1. Overexpression of GDAP1 in HeLa cells produces a mitochondrial morphology phenotype distinct from oxidative stress-induced fragmentation; this phenotype depends on the transmembrane domain and a unique hydrophobic domain absent in canonical GSTs. Biochemical glutathione binding assay with recombinant GDAP1; structural analysis; α-loop mutagenesis; GDAP1 overexpression mitochondrial morphology assay; domain deletion experiments FASEB journal High 32274853
2021 Crystal structure of the complete human GDAP1 core domain reveals a novel dimerization mode within the GST family. The long GDAP1-specific insertion forms an extended helix and a flexible loop. GDAP1 is catalytically inactive toward classical GST substrates. A fatty acid ligand (hexadecanedioic acid) binds to a pocket adjacent to a CMT-linked residue cluster, increases protein stability, and induces changes in protein conformation and oligomerization. GDAP1L1 (the closest GDAP1 homologue) is monomeric in full-length form. X-ray crystallography of human GDAP1 core domain; metabolite screening; GST substrate activity assay; thermal stability assay; analytical ultracentrifugation for oligomeric state Frontiers in molecular biosciences High 33585569
2014 In Gdap1 knockout embryonic motor neurons, mitochondrial axonal transport is defective, mitochondria show functional membrane abnormalities with reduced ATP production and impaired bioenergetics, and both basal and stimulated (glutamate) cytosolic Ca2+ levels are increased. GDAP1 loss reduces glutamate-stimulated respiration, suggesting that mitochondria cannot fully respond to Ca2+-mediated energy demand. Gdap1 knockout mouse; live-cell mitochondrial transport imaging in cultured embryonic motor neurons; mitochondrial membrane potential assay; Seahorse respirometry; live Ca2+ imaging with glutamate stimulation Neurobiology of disease High 33582224
2009 The transcription factor YY1 directly binds a consensus site in the GDAP1 core promoter. YY1 overexpression activates the GDAP1 promoter in a reporter gene system and increases endogenous GDAP1 mRNA. RNAi-mediated YY1 knockdown reduces GDAP1 expression. The regulatory effect is activatory in all cell lines tested. In vitro binding assay (EMSA); reporter gene (luciferase) assay; YY1 overexpression; YY1 RNAi knockdown with endogenous mRNA measurement Genomics Medium 19720140
2014 Junctophilin-1 (JPH1) can restore SOCE activity in GDAP1-silenced cells. JPH1 colocalizes with STIM1 in ER-plasma membrane puncta during Ca2+ release in a GDAP1-dependent manner. When GDAP1 p.R120W (dominant CMT mutation) is expressed, JPH1 appears retained in mitochondria rather than at ER-plasma membrane puncta. Co-expression of GDAP1 p.R120W and JPH1 p.R213P dramatically reduces SOCE, mimicking GDAP1 knockdown. GDAP1 siRNA knockdown with JPH1 rescue; SOCE measurement by Ca2+ imaging; co-localization of JPH1 with STIM1 by immunofluorescence; dominant GDAP1 mutant expression Human molecular genetics Medium 25168384
2008 In fibroblasts from CMT2K patients carrying a dominant GDAP1 C240Y mutation, mitochondrial respiratory chain complex I activity is approximately 40% lower than controls, and mitochondria are 33% larger in diameter with 20% greater mitochondrial mass, suggesting GDAP1 is involved in energy production and mitochondrial volume control. Patient-derived fibroblasts; spectrophotometric mitochondrial complex I activity assay; morphometric mitochondrial size analysis Neurogenetics Medium 19089472
2014 Altered expression of Drosophila Gdap1 (confirmed ortholog) produces changes in mitochondrial size, morphology, and distribution in a tissue-autonomous manner in muscle, and causes neuronal and muscular degeneration. Oxidative stress changes are not a primary cause but a long-term consequence of underlying mitochondrial dysfunction. Tissue-specific Drosophila Gdap1 overexpression and RNAi knockdown; mitochondrial morphology imaging; metabolic analyses; neuronal/muscular degeneration quantification Human molecular genetics Medium 25122658
2011 Some CMT mutations in GDAP1 lead to reduced protein expression and cause selective structural disruption of the Golgi apparatus, accompanied by functional disturbances within the Golgi, as detected in both yeast and human cell-based models. Expression of GDAP1 CMT mutants in yeast and human cells; Golgi morphology imaging; drug screen in yeast-based CMT-GDAP1 model International journal of molecular sciences Low 33477664
2023 Using synchrotron radiation oriented circular dichroism and small-angle X-ray scattering on GDAP1 peptides and full-length protein in lipidic environments, GDAP1 is modeled as inserting into the mitochondrial outer membrane via a single transmembrane helix flanked by two peripheral helices that interact with the outer and inner leaflets of the membrane in different orientations. Synchrotron radiation oriented circular dichroism (OCD) spectroscopy; small-angle X-ray scattering (SAXS) with lipid bilayer systems; structural modeling Biophysical chemistry Medium 37778197
2023 CMT-linked GDAP1 mutations affecting helices α3, α6, and α7 decrease thermal stability without grossly altering overall protein structure. A conserved intramolecular interaction network centered on the α6-α7 loop is critical for GDAP1 stability. Crystal structures of R120Q, A247V, and R282H variants confirm near-normal fold but reduced stability. X-ray crystallography of CMT variant proteins (R120Q, A247V, R282H); thermal stability assays (DSF); solution SAXS for R161H, H256R, R310Q, R310W variants; bioinformatics conservation analysis PloS one High 37058526
2023 GDAP1 deficiency (GDAP1-null iPSC-derived motor neurons) causes altered mitochondrial morphology with increased fragmentation, activation of autophagy and mitophagy, downregulation of Hexokinase 2 and ATP5b, increased ROS and elevated mitochondrial membrane potential, and increased innate immune response with p38 MAPK activation, collectively constituting a Redox-inflammatory axis underlying motor neuron degeneration. Gdap1 knockout iPSC-derived motor neurons; mitochondrial morphology assay; autophagy/mitophagy markers; proteomics (Western blot for HK2, ATP5b); ROS measurement; mitochondrial membrane potential assay; p38 MAPK activation assay; transcriptomic analysis Cell death discovery Medium 37393339
2025 GDAP1 knockdown in human neuronal cells increases mitochondrial turnover, biogenesis, and mitophagy, associated with increased BNIP3 and BNIP3L in mitochondrial fractions. Neural expression of human BNIP3 in Drosophila with Gdap1 knockdown reduces detrimental effects on eclosion and climbing, while simultaneous knockdown of both genes is detrimental, suggesting BNIP3-driven mitophagy acts as a partial protective mechanism against GDAP1 loss. GDAP1 siRNA knockdown in neuronal cell line; mitochondrial fraction proteomics; Drosophila neural Gdap1 knockdown with BNIP3 overexpression or simultaneous knockdown; behavioral assays Neurobiology of disease Medium 40618856
2024 GDAP1 deficiency disrupts mitochondria-peroxisome membrane contact sites (MCSs) and causes peroxisomal abnormalities reversible by PPARγ activation or glutathione supplementation. GDAP1 is identified as a tether of mitochondria-peroxisome MCSs. GSH supplementation or GDAP1 overexpression rescues these MCSs. GDAP1 deficiency in Gdap1-/- sciatic nerve causes nodes of Ranvier disruption and abnormal distribution/morphology of mitochondria, lysosomes, and peroxisomes in axons. High-resolution microscopy and live-cell imaging of MCSs in Gdap1-/- mice and patient fibroblasts; pH-sensitive fluorescent probes; transcriptomics and lipidomics; PPARγ agonist and GSH-MEE rescue experiments; sciatic nerve axon ultrastructure analysis Research square (preprint)preprint Medium 39801517
2021 The dominant GDAP1 p.T157P variant increases mitochondria-lysosome membrane contact sites correlating with hyper-fissioned mitochondria, while the recessive p.R161H variant decreases these contacts with more elongated mitochondria, indicating that GDAP1 clinical variants differentially regulate mitochondria-lysosome MCSs and Ca2+ transfer from lysosome to mitochondria. Expression of GDAP1 clinical variants in cells; live-cell imaging of mitochondria-lysosome MCSs; mitochondrial morphology assay Biology open Medium 36912213

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 GDAP1, the protein causing Charcot-Marie-Tooth disease type 4A, is expressed in neurons and is associated with mitochondria. Human molecular genetics 148 15772096
2002 Mutations in GDAP1: autosomal recessive CMT with demyelination and axonopathy. Neurology 123 12499475
2009 GDAP1 mutations differ in their effects on mitochondrial dynamics and apoptosis depending on the mode of inheritance. Neurobiology of disease 117 19782751
1993 Linkage of a locus (CMT4A) for autosomal recessive Charcot-Marie-Tooth disease to chromosome 8q. Human molecular genetics 116 8268915
2003 Mutations in the ganglioside-induced differentiation-associated protein-1 (GDAP1) gene in intermediate type autosomal recessive Charcot-Marie-Tooth neuropathy. Brain : a journal of neurology 99 12566285
2003 Evolutionary and structural analyses of GDAP1, involved in Charcot-Marie-Tooth disease, characterize a novel class of glutathione transferase-related genes. Molecular biology and evolution 87 14595091
2003 Clinical, electrophysiological and morphological findings of Charcot-Marie-Tooth neuropathy with vocal cord palsy and mutations in the GDAP1 gene. Brain : a journal of neurology 82 12821518
2010 Mitochondrial dysfunction and pathophysiology of Charcot-Marie-Tooth disease involving GDAP1 mutations. Experimental neurology 77 20849849
2008 Vocal cord paresis and diaphragmatic dysfunction are severe and frequent symptoms of GDAP1-associated neuropathy. Brain : a journal of neurology 75 18812441
2013 Silencing of the Charcot-Marie-Tooth disease-associated gene GDAP1 induces abnormal mitochondrial distribution and affects Ca2+ homeostasis by reducing store-operated Ca2+ entry. Neurobiology of disease 73 23542510
2013 Charcot-Marie-Tooth disease-associated mutants of GDAP1 dissociate its roles in peroxisomal and mitochondrial fission. EMBO reports 72 23628762
2011 Dominant GDAP1 mutations cause predominantly mild CMT phenotypes. Neurology 71 21753178
2011 Charcot-Marie-Tooth disease CMT4A: GDAP1 increases cellular glutathione and the mitochondrial membrane potential. Human molecular genetics 70 21965300
2015 Lack of GDAP1 induces neuronal calcium and mitochondrial defects in a knockout mouse model of charcot-marie-tooth neuropathy. PLoS genetics 68 25860513
2008 Mitochondrial complex I deficiency in GDAP1-related autosomal dominant Charcot-Marie-Tooth disease (CMT2K). Neurogenetics 68 19089472
2007 Cell expression of GDAP1 in the nervous system and pathogenesis of Charcot-Marie-Tooth type 4A disease. Journal of cellular and molecular medicine 63 18021315
2021 Mitochondria-lysosome membrane contacts are defective in GDAP1-related Charcot-Marie-Tooth disease. Human molecular genetics 61 33372681
2014 The Gdap1 knockout mouse mechanistically links redox control to Charcot-Marie-Tooth disease. Brain : a journal of neurology 61 24480485
2010 Phenotypical features of the p.R120W mutation in the GDAP1 gene causing autosomal dominant Charcot-Marie-Tooth disease. Journal of the peripheral nervous system : JPNS 54 21199105
2003 CMT4A: identification of a Hispanic GDAP1 founder mutation. Annals of neurology 53 12601710
2003 Phenotypical features of a Moroccan family with autosomal recessive Charcot-Marie-Tooth disease associated with the S194X mutation in the GDAP1 gene. Archives of neurology 48 12707075
2003 Variability of disease progression in a family with autosomal recessive CMT associated with a S194X and new R310Q mutation in the GDAP1 gene. Neuromuscular disorders : NMD 47 12868504
2008 A novel GDAP1 Q218E mutation in autosomal dominant Charcot-Marie-Tooth disease. Journal of human genetics 46 18231710
2003 Identification of novel GDAP1 mutations causing autosomal recessive Charcot-Marie-Tooth disease. Neuromuscular disorders : NMD 44 14561495
2014 Junctophilin-1 is a modifier gene of GDAP1-related Charcot-Marie-Tooth disease. Human molecular genetics 42 25168384
2010 The GST domain of GDAP1 is a frequent target of mutations in the dominant form of axonal Charcot Marie Tooth type 2K. Journal of medical genetics 42 20685671
2009 Targeting and function of the mitochondrial fission factor GDAP1 are dependent on its tail-anchor. PloS one 40 19340293
2016 Screening for SH3TC2 gene mutations in a series of demyelinating recessive Charcot-Marie-Tooth disease (CMT4). Journal of the peripheral nervous system : JPNS 39 27231023
2017 CMT-linked loss-of-function mutations in GDAP1 impair store-operated Ca2+ entry-stimulated respiration. Scientific reports 37 28220846
2004 Vocal cord and diaphragm paralysis, as clinical features of a French family with autosomal recessive Charcot-Marie-Tooth disease, associated with a new mutation in the GDAP1 gene. Neuromuscular disorders : NMD 36 15019704
2014 Mitochondrial defects and neuromuscular degeneration caused by altered expression of Drosophila Gdap1: implications for the Charcot-Marie-Tooth neuropathy. Human molecular genetics 35 25122658
2012 A French family with Charcot-Marie-Tooth disease related to simultaneous heterozygous MFN2 and GDAP1 mutations. Neuromuscular disorders : NMD 35 22546700
2011 A locus-specific database for mutations in GDAP1 allows analysis of genotype-phenotype correlations in Charcot-Marie-Tooth diseases type 4A and 2K. Orphanet journal of rare diseases 32 22200116
2019 Neuroinflammation in the pathogenesis of axonal Charcot-Marie-Tooth disease caused by lack of GDAP1. Experimental neurology 30 31271761
2011 Charcot-Marie-Tooth-related gene GDAP1 complements cell cycle delay at G2/M phase in Saccharomyces cerevisiae fis1 gene-defective cells. The Journal of biological chemistry 30 21890626
2016 Glutathione-conjugating and membrane-remodeling activity of GDAP1 relies on amphipathic C-terminal domain. Scientific reports 29 27841286
2013 Dominant GDAP1 founder mutation is a common cause of axonal Charcot-Marie-Tooth disease in Finland. Neurogenetics 29 23456260
2017 Distribution and genotype-phenotype correlation of GDAP1 mutations in Spain. Scientific reports 27 28751717
2023 Mutational screening of GDAP1 in dysphonia associated with Charcot-Marie-Tooth disease: clinical insights and phenotypic effects. Journal, genetic engineering & biotechnology 26 37966693
2016 Validation of differential GDAP1 DNA methylation in alcohol dependence and its potential function as a biomarker for disease severity and therapy outcome. Epigenetics 26 27128683
2004 A novel mutation of GDAP1 associated with Charcot-Marie-Tooth disease in three Italian families: evidence for a founder effect. Journal of neurology, neurosurgery, and psychiatry 24 15377708
2022 GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton. Communications biology 23 35662277
2019 Calcium Deregulation and Mitochondrial Bioenergetics in GDAP1-Related CMT Disease. International journal of molecular sciences 23 30669311
2009 Novel mutations in the GDAP1 gene in patients affected with early-onset axonal Charcot-Marie-Tooth type 4A. Neuromuscular disorders : NMD 23 19500985
2021 Mitochondria and calcium defects correlate with axonal dysfunction in GDAP1-related Charcot-Marie-Tooth mouse model. Neurobiology of disease 22 33582224
2018 A role for the GDAP1 gene in the molecular pathogenesis of Charcot‑Marie‑Tooth disease. Acta neurobiologiae experimentalis 22 29694336
2008 Two novel mutations in the GDAP1 and PRX genes in early onset Charcot-Marie-Tooth syndrome. Neuropediatrics 22 18504680
1995 Physical and genetic mapping of the CMT4A locus and exclusion of PMP-2 as the defect in CMT4A. Genomics 21 8530038
2021 GDAP1 Involvement in Mitochondrial Function and Oxidative Stress, Investigated in a Charcot-Marie-Tooth Model of hiPSCs-Derived Motor Neurons. Biomedicines 20 34440148
2015 GDAP1 mutations in Italian axonal Charcot-Marie-Tooth patients: Phenotypic features and clinical course. Neuromuscular disorders : NMD 20 26525999
2020 Structural and functional divergence of GDAP1 from the glutathione S-transferase superfamily. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 19 32274853
2018 Genotype-phenotype correlation and frequency of distribution in a cohort of Chinese Charcot-Marie-Tooth patients associated with GDAP1 mutations. Journal of neurology 17 29372391
2007 GDAP1 mutations in Czech families with early-onset CMT. Neuromuscular disorders : NMD 17 17433678
2017 A Drosophila model of GDAP1 function reveals the involvement of insulin signalling in the mitochondria-dependent neuromuscular degeneration. Biochimica et biophysica acta. Molecular basis of disease 16 28065847
2011 A new missense GDAP1 mutation disturbing targeting to the mitochondrial membrane causes a severe form of AR-CMT2C disease. Neurogenetics 16 21365284
2010 L239F founder mutation in GDAP1 is associated with a mild Charcot-Marie-Tooth type 4C4 (CMT4C4) phenotype. Neurogenetics 16 20232219
2021 Clinical and Neuroimaging Features in Charcot-Marie-Tooth Patients with GDAP1 Mutations. Journal of clinical neurology (Seoul, Korea) 14 33480199
2019 Novel GDAP1 Mutation in a Vietnamese Family with Charcot-Marie-Tooth Disease. BioMed research international 14 31179332
2017 Clinical and mutational spectrum of Japanese patients with Charcot-Marie-Tooth disease caused by GDAP1 variants. Clinical genetics 14 28244113
2014 Exome sequencing reveals mutations in MFN2 and GDAP1 in severe Charcot-Marie-Tooth disease. Journal of the peripheral nervous system : JPNS 14 25403865
2009 YY1-dependent transcriptional regulation of the human GDAP1 gene. Genomics 14 19720140
2021 Mutations in GDAP1 Influence Structure and Function of the Trans-Golgi Network. International journal of molecular sciences 13 33477664
2021 Structure of the Complete Dimeric Human GDAP1 Core Domain Provides Insights into Ligand Binding and Clustering of Disease Mutations. Frontiers in molecular biosciences 12 33585569
2020 Pathogenic Effect of GDAP1 Gene Mutations in a Yeast Model. Genes 12 32183277
2011 Two recessive intermediate Charcot-Marie-Tooth patients with GDAP1 mutations. Journal of the peripheral nervous system : JPNS 12 21692914
2023 Differential effects of Mendelian GDAP1 clinical variants on mitochondria-lysosome membrane contacts sites. Biology open 11 36912213
2023 Rapid degeneration of iPSC-derived motor neurons lacking Gdap1 engages a mitochondrial-sustained innate immune response. Cell death discovery 11 37393339
2012 A novel autosomal dominant GDAP1 mutation in an Italian CMT2 family. Journal of the peripheral nervous system : JPNS 11 22971097
2005 Autosomal recessive axonal form of Charcot-Marie-Tooth Disease caused by compound heterozygous 3'-splice site and Ser130Cys mutation in the GDAP1 gene. Neuropediatrics 11 15944907
2005 A novel Met116Thr mutation in the GDAP1 gene in a Polish family with the axonal recessive Charcot-Marie-Tooth type 4 disease. Journal of the neurological sciences 11 16343542
2014 A severe recessive and a mild dominant form of Charcot-Marie-Tooth disease associated with a newly identified Glu222Lys GDAP1 gene mutation. Acta biochimica Polonica 10 25337607
2007 Charcot-Marie-Tooth disease type 4C4 caused by a novel Pro153Leu substitution in the GDAP1 gene. Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology 10 18421898
1998 Fine localization of the CMT4A locus using a PAC contig and haplotype analysis. Neurogenetics 10 9933296
2015 Mitochondrial Dysfunction in a Patient with 8q21.11 Deletion and Charcot-Marie-Tooth Disease Type 2K due to GDAP1 Haploinsufficiency. Molecular syndromology 9 26648837
2007 A novel GDAP1 mutation P78L responsible for CMT4A disease in three Moroccan families. The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 9 18062449
2023 Amlexanox: Readthrough Induction and Nonsense-Mediated mRNA Decay Inhibition in a Charcot-Marie-Tooth Model of hiPSCs-Derived Neuronal Cells Harboring a Nonsense Mutation in GDAP1 Gene. Pharmaceuticals (Basel, Switzerland) 8 37513945
2022 One PMP22/MPZ and Three MFN2/GDAP1 Concomitant Variants Occurred in a Cohort of 189 Chinese Charcot-Marie-Tooth Families. Frontiers in neurology 8 35153971
2006 A novel GDAP1 mutation 439delA is associated with autosomal recessive CMT disease. The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 8 17001820
2006 Early onset Charcot-Marie-Tooth disease caused by a homozygous Leu239Phe mutation in the GDAP1 gene. Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology 8 17039978
2020 Cigarette smoke exposure has region-specific effects on GDAP1 expression in mouse hippocampus. Psychiatry research 7 32438208
2020 Deep geno- and phenotyping in two consanguineous families with CMT2 reveals HADHA as an unusual disease-causing gene and an intronic variant in GDAP1 as an unusual mutation. Journal of neurology 7 32897397
2009 Novel GDAP1 mutation in a Turkish family with CMT2K (CMT2K with novel GDAP1 mutation). Neuromolecular medicine 7 19381883
2008 A novel mutation in the GDAP1 gene is associated with autosomal recessive Charcot-Marie-Tooth disease in an Amish family. Clinical genetics 7 18492089
2008 Clinical, electrophysiological and genetic studies of two families with mutations in the GDAP1 gene. Neuropediatrics 7 18991200
2021 GDAP1 mutations are frequent among Brazilian patients with autosomal recessive axonal Charcot-Marie-Tooth disease. Neuromuscular disorders : NMD 6 33903021
2020 Identification and functional characterization of novel GDAP1 variants in Chinese patients with Charcot-Marie-Tooth disease. Annals of clinical and translational neurology 6 33136338
2018 WES homozygosity mapping in a recessive form of Charcot-Marie-Tooth neuropathy reveals intronic GDAP1 variant leading to a premature stop codon. Neurogenetics 6 29396836
2017 Phenotypical features of a new dominant GDAP1 pathogenic variant (p.R226del) in axonal Charcot-Marie-Tooth disease. Neuromuscular disorders : NMD 6 28236508
2023 Conserved intramolecular networks in GDAP1 are closely connected to CMT-linked mutations and protein stability. PloS one 5 37058526
2022 Structural insights into Charcot-Marie-Tooth disease-linked mutations in human GDAP1. FEBS open bio 5 35509130
2016 Generation of a disease-specific iPS cell line derived from a patient with Charcot-Marie-Tooth type 2K lacking functional GDAP1 gene. Stem cell research 5 28395795
2022 The GDAP1 p.Glu222Lys Variant-Weak Pathogenic Effect, Cumulative Effect of Weak Sequence Variants, or Synergy of Both Factors? Genes 4 36140714
2017 Pseudodominant inheritance pattern in a family with CMT2 caused by GDAP1 mutations. Journal of the peripheral nervous system : JPNS 4 28837237
2024 Abnormal redox balance at membrane contact sites causes axonopathy in GDAP1-related Charcot-Marie-Tooth disease. Research square 3 39801517
2023 Conformational analysis of membrane-proximal segments of GDAP1 in a lipidic environment using synchrotron radiation suggests a mode of assembly at the mitochondrial outer membrane. Biophysical chemistry 3 37778197
2021 Phenotype of Patients With Charcot-Marie-Tooth With the p.His123Arg Mutation in GDAP1 in Northern Finland. Neurology. Genetics 3 34632054
2015 Charcot Marie Tooth disease (CMT4A) due to GDAP1 mutation: report of a Colombian family. Colombia medica (Cali, Colombia) 3 26848201
2025 Increased BNIP3-mediated mitophagy attenuates GDAP1 loss of function - implications for Charcot-Marie-Tooth disease 4A. Neurobiology of disease 2 40618856
2024 Genetic and clinical profile of 15 Chinese families with GDAP1-related Charcot-Marie-Tooth disease and identification of H256R as a frequent mutation. Journal of the peripheral nervous system : JPNS 2 38705839
2022 Autosomal dominant GDAP1 mutation with severe phenotype and respiratory involvement: A case report. Frontiers in neurology 2 36353131

Missed literature

Know a paper Affinage missed for GDAP1? Flag it for the maintainers and the community.

No submissions yet.