Affinage

KIF5A

Kinesin heavy chain isoform 5A · UniProt Q12840

Length
1032 aa
Mass
117.4 kDa
Annotated
2026-06-10
93 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KIF5A is a neuron-enriched kinesin-1 heavy chain that powers anterograde axonal transport of multiple cargoes and is required for axon and neuron survival (PMID:12682084, PMID:39644980). Loss-of-function studies establish a broad cargo repertoire: neurofilament subunits transported by slow axonal transport (PMID:12682084), mitochondria whose motility KIF5A bidirectionally controls in motor neurons and retinal ganglion cells (PMID:22466687, PMID:35259089, PMID:36862119), GABA-A receptors delivered to the neuronal surface via the GABARAP adaptor (PMID:23217743), and SFPQ-RNA granules carried within a tetrameric complex with the KLC1 adaptor (PMID:33284322). Cargo specificity is encoded in the C-terminal tail domain, as domain-swap rescue experiments demonstrate (PMID:25355224), and KIF5A also transports collagen-1 vesicles in non-neuronal mesothelial cells (PMID:28676645). The motor adopts an autoinhibited compact bent conformation involving contacts between the motor domain, coiled-coil 1, and the proximal IAK-containing C-terminus (PMID:38309508). Two genetically distinct disease mechanisms emerge. SPG10/CMT2 mutations in the motor and neck domain abolish processive movement and microtubule-stimulated activity, acting through dominant-negative reduction of cargo flux and loss of microtubule colocalization (PMID:12355402, PMID:18203753, PMID:40945307), and impair SFPQ-motor complex binding (PMID:33284322). In contrast, ALS-linked exon-27-skipping mutations relieve autoinhibition to produce a constitutively active, hyperprocessive, self-associating motor that aggregates and is neurotoxic in vivo (PMID:35385738, PMID:35735139); the aberrant basic-pI C-terminus drives this aggregation and the cytoplasmic mislocalization of TDP-43 (PMID:40555518), while enhanced gain-of-function RNA binding mislocalizes synaptic ribosomal protein mRNAs and induces hyperexcitability (PMID:41279899). KIF5A expression is itself regulated downstream of SMN, which stabilizes KIF5A mRNA and links it to spinal muscular atrophy pathophysiology (PMID:41885937).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2002 Medium

    Established KIF5A as a disease gene and tied its motor function to axonal transport by showing a motor-domain mutation that blocks microtubule-stimulated ATPase activity causes SPG10.

    Evidence Human linkage/sequencing with functional inference from orthologous kinesin biochemistry

    PMID:12355402

    Open questions at the time
    • ATPase defect inferred from ortholog rather than measured on human KIF5A
    • no direct cargo or transport assay in this study
  2. 2003 High

    Defined the first physiological cargo by showing KIF5A is required for slow axonal transport of neurofilaments in vivo, distinguishing it from fast transport.

    Evidence Neuron-specific conditional KIF5A knockout mouse with neurofilament accumulation and axon caliber morphometry

    PMID:12682084

    Open questions at the time
    • mechanism of neurofilament cargo coupling not defined
    • did not address other cargoes
  3. 2008 High

    Resolved how SPG10 mutations act mechanistically, revealing two distinct dominant-negative modes (slowed transport vs. reduced cargo microtubule binding) at single-molecule resolution.

    Evidence In vitro gliding, laser-trap single-molecule, and quantum-dot mixed wild-type/mutant cargo transport assays

    PMID:18203753

    Open questions at the time
    • in vitro reconstitution may not capture neuronal regulatory context
    • did not test endogenous cargo specificity
  4. 2010 Medium

    Showed SPG10 N256S reduces neurofilament transport flux in both directions, demonstrating interdependence of anterograde and retrograde motors.

    Evidence Live-cell neurofilament transport imaging in mutant-expressing cortical neurons

    PMID:21087519

    Open questions at the time
    • single method, single lab
    • molecular basis of bidirectional coupling unresolved
  5. 2012 High

    Expanded the cargo repertoire and disease relevance by establishing KIF5A in mitochondrial transport and in GABA-A receptor surface delivery via GABARAP, with epileptic phenotypes.

    Evidence Constitutive and conditional KIF5A knockout mice, co-IP with GABARAP, surface biotinylation, EEG, and live mitochondrial imaging; Drosophila SPG10 genetic epistasis

    PMID:22466687 PMID:23209432 PMID:23217743

    Open questions at the time
    • structural basis of GABARAP binding not defined
    • whether SPG10 is purely dominant-negative vs. haploinsufficient debated across models
  6. 2014 High

    Localized cargo specificity to the C-terminal tail by showing only motors carrying the Kif5Aa C-tail rescue the mitochondrial transport and axon degeneration phenotype.

    Evidence Zebrafish kif5Aa mutant chimeric rescue and genetic epistasis with live mitochondrial imaging

    PMID:25355224

    Open questions at the time
    • specific tail-domain adaptors for mitochondria not identified
    • model-organism ortholog
  7. 2017 Medium

    Extended KIF5A function beyond neurons by identifying it as the motor for procollagen-1 vesicle transport and secretion in mesothelial cells.

    Evidence Super-resolution and proximity-ligation imaging, siRNA knockdown, live co-imaging of GFP-KIF5A and collagen-1

    PMID:28676645

    Open questions at the time
    • cargo adaptor for collagen vesicles unknown
    • single non-neuronal cell type
  8. 2018 Medium

    Identified C-terminal splice-site/exon-27 mutations as a familial ALS mechanism, initially framed as loss-of-function via haploinsufficiency.

    Evidence Whole exome sequencing, rare-variant burden analysis, and patient lymphoblast mRNA/splice analysis

    PMID:29342275

    Open questions at the time
    • loss-of-function interpretation later complicated by gain-of-function findings
    • patient cells not motor neurons
  9. 2021 High

    Defined the SFPQ-RNA granule transport pathway by identifying a KIF5A/KLC1/SFPQ tetrameric complex required for axon survival, and showed CMT mutations disrupt it.

    Evidence Co-IP of the tetrameric complex, loss-of-function axon degeneration assay, disease-mutation validation, and local-translation rescue

    PMID:33284322

    Open questions at the time
    • RNA content of granules not fully cataloged
    • stoichiometry within the complex not resolved
  10. 2022 High

    Reframed the ALS mechanism as toxic gain-of-function by showing exon-27-skip mutants relieve autoinhibition to become constitutively active, hyperprocessive, self-associating, aggregation-prone, and neurotoxic across systems.

    Evidence Single-molecule motility and processivity assays with purified protein, EM of aggregates, co-IP and RNA profiling, and Drosophila and C. elegans models

    PMID:35385738 PMID:35430760 PMID:35735139

    Open questions at the time
    • how hyperactivity translates to cell death not fully defined
    • relative contribution of transport dysregulation vs. aggregation unresolved
  11. 2022 Medium

    Linked KIF5A to excitatory/inhibitory balance and to neurodegeneration via mitochondrial transport, showing it differentially routes GABA-A vs. AMPA receptors in seizure and is required for retinal ganglion cell survival.

    Evidence Co-IP in seizure models with receptor recycling/surface assays; in vivo RGC knockout/knockdown/overexpression with mitochondrial transport imaging

    PMID:35259089 PMID:36388788

    Open questions at the time
    • mechanism of receptor-selectivity switching unknown
    • single-lab disease-model contexts
  12. 2023 High

    Established cargo-selective transport deficits in human cells and uncovered upstream regulation of KIF5A by TLR7/autophagy signaling affecting inhibitory transmission.

    Evidence KIF5A-null iPSC motor neurons with cargo-specific live imaging (mitochondria, SFPQ granules, neurofilaments); TLR7 KO mice with co-IP and seizure assays; Drosophila ΔExon27 motor-neuron model; RGC bidirectional manipulation

    PMID:36862119 PMID:37258573 PMID:37748861 PMID:39644980

    Open questions at the time
    • why neurofilament transport is spared in human iPSC neurons unexplained
    • direct regulators of KIF5A expression beyond TLR7 incomplete
  13. 2024 Medium

    Provided a structural basis for autoinhibition, defining the compact bent conformation and showing the ALS exon-27-skip mutant retains but destabilizes this state.

    Evidence Negative-stain EM, crosslinking mass spectrometry, and AlphaFold2 modeling of the full-length homodimer

    PMID:38309508

    Open questions at the time
    • specific autoinhibitory contacts not validated by mutagenesis
    • no high-resolution structure
  14. 2025 Medium

    Elucidated the molecular driver of ALS aggregation and RNA-based gain-of-function, showing the basic-pI C-terminus causes aggregation and TDP-43 mislocalization and that enhanced mRNA binding mislocalizes synaptic ribosomal transcripts.

    Evidence pI-engineered KIF5A variants in iPSC motor neurons, TDP-43 immunofluorescence, CLIP/RNA-IP, electrophysiology, and stress-granule co-IP (one preprint)

    PMID:40555518 PMID:41279899 PMID:41836882

    Open questions at the time
    • RNA-binding mechanism of an otherwise non-RNA-binding motor not structurally defined
    • link between aggregation and transport failure quantitatively unresolved
  15. 2025 Medium

    Placed KIF5A within an SMN-dependent pathway and refined the SPG10 mechanism with tunable mechanochemistry and isogenic disease models.

    Evidence SMN RNA-IP and SMA rescue experiments; isogenic CRISPR SPG10 iPSC motor neurons with cargo transport imaging; cross-species single-molecule and structural ADP-release analysis (one preprint)

    PMID:40654747 PMID:40945307 PMID:41836058 PMID:41885937

    Open questions at the time
    • how SMN-dependent KIF5A regulation intersects ALS gain-of-function unclear
    • ADP-release tuning not tested in disease context

Open questions

Synthesis pass · forward-looking unresolved questions
  • How autoinhibition is physiologically relieved at cargo-loading sites, and how a hyperactive aggregating motor causes selective motor-neuron death, remain the central open mechanistic questions.
  • no high-resolution structure of the activated cargo-bound motor
  • causal chain from ΔExon27 hyperactivity/aggregation to neurodegeneration unresolved
  • adaptors linking the tail to most cargoes incompletely defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003774 cytoskeletal motor activity 4 GO:0008092 cytoskeletal protein binding 3 GO:0003723 RNA binding 2 GO:0060090 molecular adaptor activity 2 GO:0140657 ATP-dependent activity 2
Localization
GO:0005829 cytosol 3 GO:0005856 cytoskeleton 2
Pathway
R-HSA-1643685 Disease 4 R-HSA-9609507 Protein localization 4 R-HSA-112316 Neuronal System 3 R-HSA-5653656 Vesicle-mediated transport 3
Partners
G3BP1GABARAPGABRB2GLUR2KLC1SFPQSMNTDP-43
Complex memberships
KIF5A/KLC1/SFPQ transport complex

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 A missense mutation (N256S) in the KIF5A motor domain at an invariant asparagine residue prevents stimulation of the motor ATPase by microtubule-binding, establishing KIF5A as the causal gene for hereditary spastic paraplegia SPG10 and implicating impaired anterograde axoplasmic transport in its pathogenesis. Human genetics (linkage, sequencing) combined with functional inference from orthologous kinesin mutation studies showing loss of microtubule-stimulated ATPase activity American journal of human genetics Medium 12355402
2003 Neuron-specific conditional knockout of KIF5A in mice causes accumulation of neurofilament subunits (NF-H, NF-M, NF-L) in peripheral sensory neuron cell bodies with reduction in axon caliber, establishing KIF5A as required for slow axonal transport of neurofilaments while leaving fast axonal transport largely intact. Conditional knockout mouse (synapsin-Cre × floxed KIF5A), immunostaining, axon caliber morphometry The Journal of cell biology High 12682084
2008 SPG10 point mutations in the KIF5A motor/neck domain reduce microtubule affinity and/or gliding velocity; in single-molecule laser-trapping assays none of the mutants (N256S, K253N, R280C, A361V) move processively; in mixed-motor assays N256S reduces gross cargo flux by slowing transport while K253N and R280C reduce microtubule binding of cargo, revealing two distinct dominant-negative mechanisms underlying SPG10. In vitro microtubule gliding assay, laser-trapping single-molecule assay, quantum-dot cargo transport assay with heterodimeric wild-type/mutant mixtures Human molecular genetics High 18203753
2010 The SPG10 mutation N256S in kinesin-1A (KIF5A) decreases both anterograde and retrograde neurofilament transport flux in cultured cortical neurons by reducing the frequency of anterograde and retrograde movements; anterograde velocity is unchanged while retrograde velocity is increased, demonstrating interdependence of anterograde and retrograde neurofilament motors. Live-cell fluorescence imaging of neurofilament transport in mouse cortical neurons expressing N256S-KIF5A Molecular neurodegeneration Medium 21087519
2012 KIF5A knockout mouse motor neurons show reduced anterograde and retrograde mitochondrial transport velocity, reduced axon/dendrite outgrowth and branching, and reduced survival; sensory neurons show reduced neurite outgrowth but no survival deficit, indicating a cell-type-specific requirement for KIF5A in mitochondrial axonal transport. Primary neuron cultures from constitutive KIF5A−/− mice, live mitochondrial transport imaging, survival assays, morphometric analysis Neurogenetics Medium 22466687
2012 KIF5A specifically interacts with GABARAP (GABA-type-A-receptor-associated protein) and is required for neuronal surface expression of GABA-A receptors; conditional Kif5a-knockout mice show impaired GABA-A receptor-mediated synaptic transmission and epileptic EEG abnormalities, demonstrating that KIF5A mediates anterograde transport of GABA-A receptors via GABARAP. Conditional Kif5a-KO mice (neuron-specific), EEG, co-immunoprecipitation of KIF5A with GABARAP, surface biotinylation of GABA-A receptors Neuron High 23217743
2012 In a Drosophila SPG10 model, expression of the N256S Khc (KIF5A ortholog) mutation disrupts axonal transport and induces motoneuron disease; genetic analysis indicates SPG10 is caused by selective dominant-negative loss of endogenous kinesin-1 function rather than haploinsufficiency, and neurofilament-independent cargo deficits are sufficient to cause HSP-like pathology. Drosophila transgenic expression of N256S Khc, genetic epistasis, axonal transport assays, synaptic morphology and behavioral phenotyping PLoS genetics Medium 23209432
2014 Kif5Aa-specific function in mitochondrial localization in peripheral sensory axons is mediated by the KIF5A C-terminal tail domain; only Kif5Aa or chimeric motors bearing the Kif5Aa C-tail rescue the mitochondria-lacking, degenerating axon phenotype of zebrafish kif5Aa mutants, establishing cargo-specificity through the tail domain. Zebrafish kif5Aa mutant analysis, chimeric rescue constructs, cell-autonomous epistasis with kif1b and kbp, live imaging of axonal mitochondria The Journal of neuroscience High 25355224
2017 KIF5A co-localizes with collagen-1-containing vesicles in human pleural mesothelial cells, and KIF5A knockdown significantly reduces collagen-1 secretion and peripheral vesicle localization; live imaging shows KIF5A and collagen-1 vesicles move together at ~0.56 µm/sec, establishing KIF5A as the motor for procollagen vesicle transport in myofibroblast-like cells. Super-resolution structured illumination microscopy, DUO-Link proximity ligation, siRNA knockdown, live-cell co-imaging of GFP-KIF5A and mCherry-Col-1, kymography Scientific reports Medium 28676645
2018 ALS-associated KIF5A splice-site mutations in the C-terminal domain cause exon 27 skipping and haploinsufficiency of KIF5A mRNA in patient lymphoblasts, while a missense mutation (p.Arg1007Gly) upstream of the exon 27 splice donor abrogates the splice donor site and causes defective pre-mRNA splicing, establishing loss-of-function via the C-terminal domain as a mechanism in familial ALS. Whole exome sequencing, rare variant burden analysis, lymphoblast RNA/mRNA sequencing, splice-site functional analysis Brain Medium 29342275
2021 KIF5A selectively binds the RNA-binding protein SFPQ within a tetrameric complex also containing the adaptor KLC1, and this KIF5A/KLC1-mediated transport of SFPQ-RNA granules is required for axon survival; CMT-associated KIF5A mutations impair SFPQ-motor complex binding. Co-immunoprecipitation of SFPQ with KIF5A/KLC1 complex, KIF5A loss-of-function, axon degeneration assay, rescue with locally translated proteins in CMT models The Journal of cell biology High 33284322
2022 ALS-associated KIF5A ΔExon27 (exon 27 skipping) mutant is constitutively active (relieved of autoinhibition) at the single-molecule level, shows dysregulated motor activity, cellular mislocalization, altered axonal transport, altered protein and RNA interactions, and decreased neuronal survival, supporting a toxic gain-of-function mechanism. Single-molecule motility assay, neuronal survival assay, co-immunoprecipitation, RNA interaction profiling, gene expression/splicing analysis, cellular mislocalization imaging Cell reports High 35385738
2022 KIF5A ΔExon27 is prone to form oligomers and aggregates; purified ΔExon27 oligomers show more active movement on microtubules in vitro than wild-type KIF5A, and expression in C. elegans neurons causes morphological defects, indicating gain-of-function toxicity rather than simple loss-of-function. In vitro oligomerization assay, microtubule motility assay with purified protein, C. elegans neuron morphology assay Genes to cells Medium 35430760
2022 ALS-linked KIF5A ΔExon27 mutant relieves motor autoinhibition, increases motor self-association, and produces drastically enhanced processivity on microtubules; ΔExon27 is prone to form cytoplasmic aggregates and is neurotoxic in Drosophila (wing defects, motor impairment, paralysis, premature death), establishing toxic gain-of-function as the pathogenic mechanism. Single-molecule processivity assay, electron microscopy of aggregates, Drosophila transgenic overexpression with locomotion and survival readouts, patient iPSC motor neuron analysis EMBO reports High 35735139
2022 Seizure-induced changes reduce KIF5A interactions with Gabrb2/3 (GABA-A receptor subunits) while increasing KIF5A interactions with GluR2 (AMPA receptor subunit), with decreased recycling of GABA-A receptors and increased recycling of AMPA receptors to the surface, demonstrating that KIF5A differentially regulates excitatory/inhibitory receptor surface expression. Co-immunoprecipitation of KIF5A with GluR2 and Gabrb2+3 in seizure models (in vivo PTZ-rat and in vitro Mg2+-free model), receptor recycling assay, surface expression assay Annals of translational medicine Medium 36388788
2022 Kif5a knockout in retinal ganglion cells (RGCs) results in progressive RGC degeneration in the absence of injury; Kif5a knockdown reduces anterograde mitochondrial trafficking in RGCs while Kif5a overexpression enhances it, identifying Kif5a-dependent mitochondrial transport failure as a cause of RGC neurodegeneration. In vivo Kif5a KO in RGCs (AAV-Cre), quantitative transportome analysis, live mitochondrial transport imaging, progressive degeneration scoring eLife Medium 35259089
2023 In Drosophila motor neurons, KIF5A ΔExon27 expression causes locomotion deficits, disturbed distribution of mitochondria and synaptic vesicles, accumulation of KIF5A Δ27-containing inclusions in soma and axons, alterations in neuromuscular junction morphology and synaptic transmission, and motor neuron death, consistent with toxic gain-of-function. Drosophila transgenic expression of KIF5A Δ27 in motor neurons, electrophysiology at NMJ, live mitochondrial/synaptic vesicle imaging, larval locomotion assay, survival assay The Journal of neuroscience Medium 37748861
2023 TLR7 activation in neurons induces autophagy and decreases KIF5A expression, which reduces KIF5A interactions with GABARAP and GABAARβ2/3, resulting in impaired GABA-A receptor transport and abnormal inhibitory postsynaptic transmission, increasing seizure susceptibility. TLR7 KO mice, co-immunoprecipitation of KIF5A with GABARAP and GABAARβ2/3, seizure susceptibility assay, autophagy induction assay Experimental & molecular medicine Medium 37258573
2023 KIF5A deficiency in human iPSC-derived motor neurons reduces neurite complexity at DIV14, impairs axonal regeneration, decreases mitochondria motility and anterograde speed at DIV42, and strongly reduces anterograde transport of SFPQ-associated RNA granules at DIV42, with no effect on neurofilament transport. KIF5A null iPSC-derived human motor neurons, live axonal transport imaging of mitochondria, SFPQ granules, and neurofilaments, axonal regeneration assay Neurobiology of disease High 39644980
2023 Kif5a knockdown in developing retinal ganglion cells decreases anterograde mitochondrial transport while Kif5a overexpression increases mitochondrial motility and anterograde transport, directly establishing Kif5a as a regulator of mitochondrial axonal transport in developing RGCs. shRNA knockdown and AAV overexpression in primary rat RGCs, MitoTracker live-cell imaging with kymography Investigative ophthalmology & visual science Medium 36862119
2024 Full-length autoinhibited KIF5A homodimer adopts a compact bent conformation through a bend between coiled-coils 2 and 3 around P687; crosslinking mass spectrometry reveals interactions between motor domain, coiled-coil 1, and the proximal C-terminal IAK-containing region, but not the distal C-terminal tail; the ALS exon-27-skip mutant retains autoinhibited molecules but its autoinhibited state is more labile. Negative-stain electron microscopy, crosslinking mass spectrometry (XL-MS), AlphaFold2 structure prediction of full-length KIF5A homodimer The Journal of biological chemistry Medium 38309508
2025 ALS-related KIF5A ΔExon27 mutant protein accumulates in human iPSC-derived motor neurons, induces cytoplasmic mislocalization of TDP-43 (an ALS hallmark), and this is exacerbated by overexpression; the altered C-terminal sequence has a basic isoelectric point (unlike acidic WT), and engineering a mutant retaining the aberrant sequence but with lower pI reduces protein aggregation and TDP-43 mislocalization, demonstrating that the isoelectric shift drives KIF5A aggregation and TDP-43 pathology. iPSC-derived motor neuron overexpression, pI-modified KIF5A variants, immunofluorescence for TDP-43 localization and KIF5A aggregation, primary neuron overexpression The Journal of neuroscience Medium 40555518
2025 FAK signaling promotes KIF5A expression and neuronal differentiation by downregulating epigenetic modifiers DNMT1 and KDM5A; FAK activity is phosphorylation-dependent and required for KIF5A upregulation, which in turn regulates mitochondrial dynamics during differentiation. FAK inhibition/activation, DNMT1/KDM5A knockdown, KIF5A overexpression/knockdown, mitochondrial morphology assay in differentiating neurons FEBS letters Low 41084333
2025 SMN protein associates with KIF5A mRNA and contributes to its stability; SMN deficiency in human neurons and SMA mouse models downregulates KIF5A, and KIF5A overexpression rescues impaired axon regeneration caused by SMN loss, placing KIF5A downstream of SMN in a pathway linking SMA and ALS pathophysiology. RNA immunoprecipitation of SMN with KIF5A mRNA, SMN knockdown in human neurons and SMA mouse model, KIF5A overexpression rescue of axon regeneration JCI insight Medium 41885937
2025 KIF5A mutations causing ALS (exon 27 skipping) abolish KIF5A axonal interaction with SFPQ cargo and, under stress conditions, iPSC-derived motor neurons carrying an intronic KIF5A variant (c.2993-6C>A) exhibit TDP-43 proteinopathy, linking KIF5A ΔExon27-mediated cargo transport failure to TDP-43 pathology. iPSC-derived motor neurons from patients and controls, RT-PCR for exon 27 splicing, immunofluorescence for KIF5A-SFPQ axonal colocalization and TDP-43 localization under stress Neurology. Genetics Medium 41836882
2025 KIF5A directly binds mRNAs encoding synaptic ribosomal proteins and is required for their synaptic localization and normal synaptic composition and function; KIF5A also binds G3BP1 and stress granule-associated proteins; ALS-linked KIF5A mutations enhance mRNA binding, increase synaptic ribosomal protein accumulation, induce neuronal hyperexcitability, and impair stress responses—a gain-of-function RNA-binding mechanism. CLIP/RNA immunoprecipitation, KIF5A loss-of-function, ALS mutant overexpression in patient iPSC motor neurons, electrophysiology, stress granule co-IP bioRxivpreprint Medium 41279899
2025 KIF5A from giraffes and pythons moves 25% faster than mouse KIF5A on neuronal microtubules due to three amino acid substitutions (R114Q, S155A, Y309F); structural analysis reveals accelerated ADP release underlies enhanced velocity; the motor generates less force but maintains cargo transport under load and exerts less drag in multi-motor environments—demonstrating that the KIF5A mechanochemical cycle is tunable and that ADP release rate is rate-limiting for velocity. In vitro single-molecule motility assay, live imaging in cultured mouse hippocampal neurons, cryo-EM/structural analysis, site-directed mutagenesis of velocity-determining residues bioRxivpreprint Medium 40654747
2025 SPG10 mutations in KIF5A cause loss of colocalization with α-tubulin; a splice-site mutation (c.446-2A>G) destroys the donor site leading to exon 6 skipping producing truncated proteins with reduced expression that lose microtubule colocalization, while four missense mutations retain normal mRNA/protein levels but also lose α-tubulin colocalization, indicating that both haploinsufficiency and abnormal subcellular localization underlie SPG10. In vitro minigene splicing assay, protein expression analysis, immunofluorescence co-localization with α-tubulin in transfected cells, iPSC motor neuron functional validation Parkinsonism & related disorders Medium 40945307
2026 The SPG10 variant p.R17Q in the KIF5A motor domain (predicted to affect ATP binding) causes increased KIF5A distribution in distal neurites with neurofilament-positive axonal swellings, and significantly reduces anterograde velocity and distance of mitochondria and lysosomes along neurites in isogenic iPSC-derived motor neurons, confirming pathogenicity and establishing defective axonal transport as the mechanism. CRISPR-Cas9 isogenic iPSC correction, live axonal transport imaging of mitochondria and lysosomes by kymography, immunofluorescence for KIF5A distribution and neurofilament swellings Frontiers in genetics Medium 41836058

Source papers

Stage 0 corpus · 93 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. Neuron 561 29566793
2002 A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10). American journal of human genetics 417 12355402
2003 Abnormal neurofilament transport caused by targeted disruption of neuronal kinesin heavy chain KIF5A. The Journal of cell biology 272 12682084
2018 Hot-spot KIF5A mutations cause familial ALS. Brain : a journal of neurology 192 29342275
2012 Molecular motor KIF5A is essential for GABA(A) receptor transport, and KIF5A deletion causes epilepsy. Neuron 137 23217743
2011 Mutations in the motor and stalk domains of KIF5A in spastic paraplegia type 10 and in axonal Charcot-Marie-Tooth type 2. Clinical genetics 128 21623771
2009 Complicated forms of autosomal dominant hereditary spastic paraplegia are frequent in SPG10. Human mutation 112 18853458
2008 Effect of spastic paraplegia mutations in KIF5A kinesin on transport activity. Human molecular genetics 112 18203753
2014 Unique function of Kinesin Kif5A in localization of mitochondria in axons. The Journal of neuroscience : the official journal of the Society for Neuroscience 102 25355224
2004 Evidence of kinesin heavy chain (KIF5A) involvement in pure hereditary spastic paraplegia. Neurology 89 15452312
2022 ALS-associated KIF5A mutations abolish autoinhibition resulting in a toxic gain of function. Cell reports 83 35385738
2010 The autoimmune disease-associated KIF5A, CD226 and SH2B3 gene variants confer susceptibility for multiple sclerosis. Genes and immunity 78 20508602
2012 Axonal transport deficit in a KIF5A( -/- ) mouse model. Neurogenetics 68 22466687
2020 KIF5A-dependent axonal transport deficiency disrupts autophagic flux in trimethyltin chloride-induced neurotoxicity. Autophagy 62 32160081
2010 A hereditary spastic paraplegia mutation in kinesin-1A/KIF5A disrupts neurofilament transport. Molecular neurodegeneration 62 21087519
2021 Binding and transport of SFPQ-RNA granules by KIF5A/KLC1 motors promotes axon survival. The Journal of cell biology 56 33284322
2022 ALS-linked KIF5A ΔExon27 mutant causes neuronal toxicity through gain-of-function. EMBO reports 54 35735139
2016 KIF5A mutations cause an infantile onset phenotype including severe myoclonus with evidence of mitochondrial dysfunction. Annals of neurology 51 27463701
2012 Identification of a functional variant in the KIF5A-CYP27B1-METTL1-FAM119B locus associated with multiple sclerosis. Journal of medical genetics 50 23160276
2012 Spastic paraplegia mutation N256S in the neuronal microtubule motor KIF5A disrupts axonal transport in a Drosophila HSP model. PLoS genetics 47 23209432
2006 A missense mutation in the coiled-coil domain of the KIF5A gene and late-onset hereditary spastic paraplegia. Archives of neurology 47 16476820
2022 An ALS-associated KIF5A mutant forms oligomers and aggregates and induces neuronal toxicity. Genes to cells : devoted to molecular & cellular mechanisms 45 35430760
2006 Mutation in KIF5A can also cause adult-onset hereditary spastic paraplegia. Neurogenetics 44 16489470
2008 SPG10 is a rare cause of spastic paraplegia in European families. Journal of neurology, neurosurgery, and psychiatry 39 18245137
2016 KIF5A de novo mutation associated with myoclonic seizures and neonatal onset progressive leukoencephalopathy. Clinical genetics 38 27414745
2018 Kinesin-1 Proteins KIF5A, -5B, and -5C Promote Anterograde Transport of Herpes Simplex Virus Enveloped Virions in Axons. Journal of virology 36 30068641
2022 Quantitative transportomics identifies Kif5a as a major regulator of neurodegeneration. eLife 31 35259089
2017 Wide phenotypic spectrum in axonal Charcot-Marie-Tooth neuropathy type 2 patients with KIF5A mutations. Genes & genomics 31 29892902
2016 Axonal motor protein KIF5A and associated cargo deficits in multiple sclerosis lesional and normal-appearing white matter. Neuropathology and applied neurobiology 24 26785938
2023 ALS-Associated KIF5A Mutation Causes Locomotor Deficits Associated with Cytoplasmic Inclusions, Alterations of Neuromuscular Junctions, and Motor Neuron Loss. The Journal of neuroscience : the official journal of the Society for Neuroscience 22 37748861
2018 Mutation analysis of KIF5A in Chinese amyotrophic lateral sclerosis patients. Neurobiology of aging 22 30301576
2010 A novel mutation in KIF5A gene causing hereditary spastic paraplegia with axonal neuropathy. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 22 21107874
2012 Role of kinesin-1 in the pathogenesis of SPG10, a rare form of hereditary spastic paraplegia. The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry 21 22785106
2018 A Novel Mutation in the Stalk Domain of KIF5A Causes a Slowly Progressive Atypical Motor Syndrome. Journal of clinical medicine 20 30583522
2017 KIF5A transports collagen vesicles of myofibroblasts during pleural fibrosis. Scientific reports 18 28676645
2020 Genetic and functional analysis of KIF5A variants in Japanese patients with sporadic amyotrophic lateral sclerosis. Neurobiology of aging 17 32888732
2019 KIF5A Promotes Bladder Cancer Proliferation In Vitro and In Vivo. Disease markers 17 31354888
2024 A multiscale approach reveals the molecular architecture of the autoinhibited kinesin KIF5A. The Journal of biological chemistry 16 38309508
2016 Late-onset spastic paraplegia type 10 (SPG10) family presenting with bulbar symptoms and fasciculations mimicking amyotrophic lateral sclerosis. Journal of the neurological sciences 16 27084214
2015 A novel mutation in motor domain of KIF5A associated with an HSP/axonal neuropathy phenotype. Journal of clinical neuromuscular disease 15 25695920
2015 Identification of two novel KIF5A mutations in hereditary spastic paraplegia associated with mild peripheral neuropathy. Journal of the neurological sciences 15 26403765
2023 Impaired motor unit recovery and maintenance in a knock-in mouse model of ALS-associated Kif5a variant. Neurobiology of disease 14 37164288
2017 A novel mutation in KIF5A in a Malian family with spastic paraplegia and sensory loss. Annals of clinical and translational neurology 14 28382308
2022 The recycling of AMPA receptors/GABAa receptors is related to neuronal excitation/inhibition imbalance and may be regulated by KIF5A. Annals of translational medicine 13 36388788
2024 KIF5A regulates axonal repair and time-dependent axonal transport of SFPQ granules and mitochondria in human motor neurons. Neurobiology of disease 12 39644980
2018 KIF5A and ALS2 Variants in a Family With Hereditary Spastic Paraplegia and Amyotrophic Lateral Sclerosis. Frontiers in neurology 12 30581417
2023 Activation of TLR7-mediated autophagy increases epileptic susceptibility via reduced KIF5A-dependent GABAA receptor transport in a murine model. Experimental & molecular medicine 10 37258573
2014 A novel KIF5A mutation in an Italian family marked by spastic paraparesis and congenital deafness. Journal of the neurological sciences 10 24939576
2012 Novel SPG10 mutation associated with dysautonomia, spinal cord atrophy, and skin biopsy abnormality. European journal of neurology 10 22788249
2023 Kif5a Regulates Mitochondrial Transport in Developing Retinal Ganglion Cells In Vitro. Investigative ophthalmology & visual science 9 36862119
2021 KIF5A and the contribution of susceptibility genotypes as a predictive biomarker for multiple sclerosis. Journal of neurology 9 33484325
2023 A human proteogenomic-cellular framework identifies KIF5A as a modulator of astrocyte process integrity with relevance to ALS. Communications biology 8 37386082
2023 Computational study of the motor neuron protein KIF5A to identify nsSNPs, bioactive compounds, and its key regulators. Frontiers in genetics 7 38028604
2018 A novel KIF5A gene variant causes spastic paraplegia and cerebellar ataxia. Annals of clinical and translational neurology 7 30480035
2024 Paraquat disrupts KIF5A-mediated axonal mitochondrial transport in midbrain neurons and its antagonism by melatonin. The Science of the total environment 6 38750743
2023 Expanding the spectrum of KIF5A mutations-case report of a large kindred with familial ALS and overlapping syndrome. Amyotrophic lateral sclerosis & frontotemporal degeneration 6 36604770
2023 Heterogeneous splicing patterns resulting from KIF5A variants associated with amyotrophic lateral sclerosis. Human molecular genetics 6 37593923
2015 Progressive Lower Extremity Weakness and Axonal Sensorimotor Polyneuropathy from a Mutation in KIF5A (c.611G>A;p.Arg204Gln). Case reports in genetics 6 26543653
2024 FOXP3 targets KIF5A to increase lactate production and promote docetaxel resistance in lung adenocarcinoma. Acta biochimica et biophysica Sinica 5 38798241
2022 HIF‑1α protects PC12 cells from OGD/R‑induced cell injury by regulating autophagy flux through the miR‑20a‑5p/KIF5A axis. Acta neurobiologiae experimentalis 5 36214718
2022 Generation of an iPSC line from a patient with spastic paraplegia type 10 carrying a novel mutation in KIF5A gene. Stem cell research 5 36565680
2021 Preliminary report for Epilepsia Open A case of West syndrome with severe global developmental delay and confirmed KIF5A gene variant. Epilepsia open 5 33681666
2018 Mutation in KIF5A c.610C>T Causing Hereditary Spastic Paraplegia with Axonal Sensorimotor Neuropathy. Case reports in neurology 5 30057544
2025 One gene, many phenotypes: the role of KIF5A in neurodegenerative and neurodevelopmental diseases. Cell communication and signaling : CCS 4 40524150
2024 Ergotamine Targets KIF5A to Facilitate Anoikis in Lung Adenocarcinoma. The clinical respiratory journal 4 39517115
2022 Lab resource: Single cell line generation and characterization of a human-derived induced pluripotent stem cell line (IGIBi005-A) from a patient with spastic paraplegia/ataxia/ALS phenotype due to the mutation of the gene Kinesin Family Member 5A (KIF5A). Stem cell research 4 36055117
2021 Sural biopsy to detect the axonal cytoskeleton defects in KIF5A-related Charcot-Marie-Tooth disease type 2. Clinical neuropathology 4 33155544
2021 New structural variations responsible for Charcot-Marie-Tooth disease: The first two large KIF5A deletions detected by CovCopCan software. Computational and structural biotechnology journal 4 34429846
2012 Transgenic medaka fish which mimic the endogenous expression of neuronal kinesin, KIF5A. Brain research 4 22975131
2024 The ALS-associated KIF5A P986L variant is not pathogenic for Drosophila motoneurons. Scientific reports 3 39174694
2018 Kinesins in neurological inherited diseases: a novel motor-domain mutation in KIF5A gene in a patient from Southern Italy affected by hereditary spastic paraplegia. Acta neurologica Belgica 3 30411208
2025 A novel antidepressant mechanism of baicalin: enhancing KIF5A-mediated axoplasmic transport and vesicular trafficking in glutamatergic neurons. Frontiers in pharmacology 2 40290440
2024 KIF5A regulates axonal repair and time-dependent axonal transport of SFPQ granules and mitochondria in human motor neurons. bioRxiv : the preprint server for biology 2 39314491
2025 KIF5A variant in familial dystonia: A clinicogenetic study of a large Roma kindred. Parkinsonism & related disorders 1 40311553
2025 ALS Mutations Shift the Isoelectric Point of the KIF5A C Terminal Inducing Protein Aggregation and TDP-43 Mislocalization. The Journal of neuroscience : the official journal of the Society for Neuroscience 1 40555518
2025 New variants and genotype-phenotype correlation in KIF5A mutation: the contribution of a large Italian cohort. Journal of medical genetics 1 40562529
2025 Enhanced axonal transport in large vertebrates: KIF5A adaptations in giraffes and pythons. bioRxiv : the preprint server for biology 1 40654747
2025 [Effects of electroacupuncture on cognitive impairment and mitophagy mediated by KIF5A/Miro1 pathway in Parkinson's disease mice]. Zhongguo zhen jiu = Chinese acupuncture & moxibustion 1 40825695
2025 Clinical and functional analysis of KIF5A related spastic paraplegia type 10. Parkinsonism & related disorders 1 40945307
2025 KIF5A upregulation by FAK-mediated downregulation of epigenetic modifiers promotes mitochondrial dynamics in neuronal differentiation. FEBS letters 1 41084333
2020 Generation of two induced pluripotent stem cell (iPSC) lines from an ALS patient with simultaneous mutations in KIF5A and MATR3 genes. Stem cell research 1 33388707
2026 Novel KIF5A variant in a patient with early-onset levodopa-responsive Parkinson's syndrome. BMJ case reports 0 41629112
2026 KIF5A and ALS: a clinical and genetic description of a case series and review of literature. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 0 41760955
2026 Functional validation of the novel KIF5A p.R17Q VUS reveals defective axonal transport in iPSC-motoneurons from a SPG10 patient. Frontiers in genetics 0 41836058
2026 Consequences of the Novel ALS-Associated KIF5A Variant c.2993-6C > A for Exon 27 Splicing and Axonal Transport of SFPQ. Neurology. Genetics 0 41836882
2026 KIF5A downregulation in spinal muscular atrophy links axonal regeneration defects with ALS. JCI insight 0 41885937
2025 A Japanese patient with hereditary spastic paraplegia with a rare KIF5A nonsense variant. Human genome variation 0 40456722
2025 KIF5A downregulation in spinal muscular atrophy links axonal regeneration defects with ALS. bioRxiv : the preprint server for biology 0 40672150
2025 Targeted plasma proteomics uncover proteins associated with KIF5A-linked SPG10 and ALS spectrum disorders. HGG advances 0 40873038
2025 MiR-140-3p regulates axonal motor protein KIF5A and contributes to axonal transport degeneration in SMA. Cell death discovery 0 41057313
2025 KIF5A binds RNA to orchestrate synaptic mRNA localization and stress granules in ALS. bioRxiv : the preprint server for biology 0 41279899
2025 Genetic and clinical characterization of SPG10: a case series of novel pathogenic variants and phenotypic diversity. Annals of medicine and surgery (2012) 0 41377335
2024 Whole-Genome Sequencing Identified a Novel Mutation in the N-Terminal Domain of KIF5A in Chinese Patients with Familial Amyotrophic Lateral Sclerosis. Genes 0 38927616

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