Affinage

ALS2

Alsin · UniProt Q96Q42

Length
1657 aa
Mass
183.6 kDa
Annotated
2026-04-28
74 papers in source corpus 26 papers cited in narrative 26 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ALS2/alsin is a multidomain guanine nucleotide exchange factor that activates Rab5 via its C-terminal VPS9 domain and Rac1 via its central DH/PH domain, coupling macropinocytosis, endosome maturation, and endolysosomal protein degradation to neuronal survival and neurite outgrowth. ALS2 functions as a Rac1 effector: activated Rac1 recruits cytoplasmic ALS2 to membrane ruffles and macropinosomes, where ALS2 then drives Rab5-dependent endosome fusion, early-to-late endosome trafficking, and amphisome formation required for autophagic clearance of ubiquitinated substrates (PMID:17409386, PMID:20339559, PMID:33683284). Homo-tetramerization through C-terminal regions and an N-terminal intrinsically disordered region is essential for Rab5 GEF activity and proper endosomal localization; disease-causing mutations uniformly destabilize the protein, disrupt oligomeric organization, or abolish endosomal targeting (PMID:15247254, PMID:30224357, PMID:34243065). Loss-of-function mutations in ALS2 cause autosomal recessive juvenile amyotrophic lateral sclerosis (ALS2) and juvenile primary lateral sclerosis, with knockout mice recapitulating upper motor neuron degeneration, Purkinje cell loss, and impaired endosomal trafficking of neurotrophic factor receptors (PMID:16321985, PMID:16802286, PMID:16769894).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2003 High

    Establishing that ALS2 is a Rab5-specific GEF acting through its VPS9 domain resolved the key question of what enzymatic activity alsin provides, directly linking the gene to endosomal biology.

    Evidence In vitro GEF assay combined with domain deletion analysis and ectopic expression in cultured cortical neurons showing Rab5/EEA1 co-localization and endosome enlargement

    PMID:12837691

    Open questions at the time
    • Crystal structure of VPS9 domain bound to Rab5 not determined
    • Whether ALS2 acts on other Rab GTPases besides Rab5 not systematically tested
  2. 2003 High

    Demonstrating that disease-causing ALS2 truncation mutants are rapidly degraded in patient lymphocytes established loss-of-function through protein instability as the universal disease mechanism, rather than a dominant-negative or gain-of-function model.

    Evidence Subcellular fractionation and protein stability assays in cultured human cells including patient-derived lymphocytes

    PMID:14668431

    Open questions at the time
    • Whether any missense mutations could act through mechanisms other than instability was not yet tested
  3. 2004 High

    Discovery that ALS2 homo-oligomerizes through its C-terminal regions and that this oligomerization is required for Rab5 GEF activity revealed that ALS2 functions as a multimer, explaining why even heterozygous truncating mutations (which disrupt oligomerization) cause complete loss of function.

    Evidence Yeast two-hybrid mapping, in vitro Rab5 GEF assay, and cell-based endosome enlargement assay with domain deletion mutants

    PMID:15247254

    Open questions at the time
    • Stoichiometry and structure of the oligomer not resolved
    • Whether oligomerization regulates DH/PH domain activity not tested
  4. 2004 High

    Identification of ALS2 as a Rac1 GEF via its DH/PH domain, with Rac1 activation mediating neuroprotection against mutant SOD1 through PI3K/Akt3, established a second catalytic output of ALS2 and linked it to motor neuron survival signaling.

    Evidence GTP-Rac1 pull-down, co-immunoprecipitation, siRNA knockdown of Rac1, and cell viability assays in NSC34 motoneuronal cells

    PMID:14970233 PMID:15579468

    Open questions at the time
    • Whether Rac1 GEF activity and Rab5 GEF activity are coordinated or independent was unclear
    • PI3K/Akt3 pathway link shown only with overexpression
  5. 2005 High

    Showing that ALS2 selectively activates Rac1 (not Rho or Cdc42), induces PAK1 kinase activity, and promotes neurite outgrowth from growth cones connected its dual GEF activities to a specific neuronal differentiation function.

    Evidence GTPase activation assays for Rac1/Rho/Cdc42, PAK1 kinase assay, immunofluorescence in growth cones, neurite outgrowth measurement

    PMID:16049005

    Open questions at the time
    • Whether PAK1 is the critical downstream effector for neurite outgrowth not established by epistasis
  6. 2005 High

    Als2-knockout mice revealed smaller endosomes, progressive Purkinje cell loss, and motor neuron disturbance in vivo, validating that ALS2 loss recapitulates features of human motor neuron disease and confirming its essential role in endosomal dynamics in intact organisms.

    Evidence Gene-targeted knockout mice with quantitative EGF-uptake analysis, immunohistochemistry, and electrophysiology

    PMID:16321985

    Open questions at the time
    • Mice showed relatively mild phenotype compared to human disease; species differences in compensation not resolved
  7. 2006 High

    Reconstitution of Rab5-dependent endosome fusion from Als2-null brain cytosol and demonstration of impaired BDNF/IGF1 receptor trafficking (but not transferrin) in primary neurons pinpointed ALS2's function to selective neurotrophic receptor endosomal transport, providing a mechanism for selective neuronal vulnerability.

    Evidence In vitro endosome fusion assay from knockout brain cytosol, live-cell receptor trafficking in primary neurons, behavioral and histological analysis

    PMID:16769894 PMID:16802286

    Open questions at the time
    • How selectivity for neurotrophic receptors over transferrin is achieved mechanistically remains unknown
  8. 2007 High

    Demonstrating that GTP-loaded Rac1 recruits ALS2 to membrane ruffles and macropinosomes, where ALS2 then uses its Rab5 GEF activity to fuse macropinosomes with endosomes, established ALS2 as a Rac1 effector that couples macropinocytosis to endosome maturation — unifying its two GEF activities into a single trafficking pathway.

    Evidence Co-immunoprecipitation with nucleotide-loaded Rac1, live-cell imaging of macropinosome dynamics, GEF-dead mutant rescue experiments

    PMID:17409386

    Open questions at the time
    • Whether Rac1-mediated recruitment involves a direct Rac1-ALS2 binding interface or adaptor proteins not determined structurally
  9. 2010 High

    Discovery that ALS2 localizes to amphisomes and is required for lysosomal clearance of LC3/p62, with Als2/SOD1 double-knockout mice showing accelerated disease and increased insoluble ubiquitinated protein, established ALS2 as a critical component of the autophagy-endolysosomal degradation axis.

    Evidence Co-localization immunofluorescence, lysosomal clearance assay, ALS2/SOD1(H46R) double-knockout mouse genetic epistasis, biochemical fractionation

    PMID:20339559 PMID:27439389

    Open questions at the time
    • Whether ALS2 directly promotes autophagosome-endosome tethering or acts indirectly through Rab5 activation not resolved
  10. 2018 High

    Characterization of pathogenic missense mutants revealed that mutations in different domains alter the wild-type tetrameric state in distinct ways — some forming larger aggregates, others dimers/trimers — yet all fail to traffic from ruffles to endosomes, unifying diverse mutations through a common trafficking-defective mechanism beyond simple instability.

    Evidence Gel-filtration chromatography, live-cell imaging upon Rac1 activation, cycloheximide chase, in silico structural mutagenesis of the RLD crystal structure

    PMID:30224357

    Open questions at the time
    • Full-length ALS2 structure not solved
    • How altered oligomeric states specifically block ruffle-to-endosome transit unclear
  11. 2021 High

    In Drosophila, ALS2 loss disrupted early-to-late endosome trafficking and postsynaptic development via the Frizzled nuclear import pathway, while also causing age-dependent neurodegeneration independently, demonstrating conserved endosomal functions and revealing a novel synaptic signaling role.

    Evidence Drosophila genetic loss-of-function with Frizzled-2 C-terminal fragment rescue, live imaging of endosomal trafficking

    PMID:33683284

    Open questions at the time
    • Whether the Frizzled nuclear import pathway connection is conserved in mammals not tested
  12. 2021 Medium

    Identification of an intrinsically disordered region within the RLD as required for proper oligomerization and endosomal localization added a new structural element beyond the VPS9 and DH/PH catalytic domains to the functional architecture of ALS2.

    Evidence IDR deletion and phospho-mimetic mutants in HeLa cells, immunofluorescence, gel-filtration chromatography

    PMID:34243065

    Open questions at the time
    • Physiological phosphorylation sites and kinases regulating ALS2 IDR not identified in vivo
    • Whether IDR mediates phase separation not tested
  13. 2022 Medium

    Discovery that brain synaptosomal ALS2 forms a CNS-specific high-molecular-weight complex beyond the cytosolic tetramer suggested that tissue-specific oligomeric states contribute to ALS2's specialized neuronal functions.

    Evidence Differential centrifugation of brain tissue with gel-filtration chromatography compared across tissues and cell types

    PMID:36459881

    Open questions at the time
    • Composition of the CNS-specific high-MW complex (additional interacting partners) unknown
    • Functional significance of higher-order complex not demonstrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full-length structure of the ALS2 tetramer, how Rab5 GEF activity is allosterically regulated by oligomerization and Rac1 binding, identification of the direct protein interactors in the CNS-specific high-molecular-weight complex, and the mechanism by which ALS2 selectively routes neurotrophic receptors versus bulk cargo through the endosomal system.
  • No full-length structural model of ALS2 oligomer
  • Allosteric coupling between Rac1 binding and Rab5 GEF activation not biochemically defined
  • Basis for selective neurotrophic receptor trafficking versus bulk endocytosis unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 6 GO:0098772 molecular function regulator activity 4
Localization
GO:0005768 endosome 7 GO:0005886 plasma membrane 3 GO:0031410 cytoplasmic vesicle 3 GO:0005829 cytosol 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 6 R-HSA-112316 Neuronal System 5 R-HSA-162582 Signal Transduction 4 R-HSA-9612973 Autophagy 3
Partners
ALS2CLPAK1RAB17RAB5ARAC1SOD1SQSTM1
Complex memberships
ALS2 homo-tetramerALS2/ALS2CL heteromeric complex

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 ALS2 protein specifically binds to small GTPase Rab5 and functions as a GEF (guanine nucleotide exchange factor) for Rab5 via its C-terminal VPS9 domain, localizes to early endosomal compartments (co-localizing with Rab5 and EEA1), and stimulates enlargement of endosomes in cultured cortical neurons. The amino-terminal RLD domain acts suppressively on membranous localization, and the DH/PH domain enhances VPS9-mediated endosome fusions. Ectopic expression in cultured neurons, co-localization with Rab5/EEA1, guanine-nucleotide exchanging reaction assay, domain deletion analysis Human molecular genetics High 12837691
2003 Endogenous ALS2 is enriched in nervous tissue and peripherally bound to the cytoplasmic face of endosomal membranes; this association requires the amino-terminal RCC1-like GEF domain. Disease-causing ALS2 mutants and the naturally truncated isoform are rapidly degraded in cultured human cells, including patient-derived lymphocytes, indicating that mutations cause loss of function through decreased protein stability. Subcellular fractionation, expression in cultured human cells including patient lymphocytes, protein stability assay Proceedings of the National Academy of Sciences of the United States of America High 14668431
2004 ALS2 forms a homophilic oligomer through its distinct C-terminal regions, and this homo-oligomerization is essential for Rab5 GEF activity in vitro and for ALS2-mediated endosome enlargement in cells. Yeast two-hybrid screen, in vitro Rab5 GEF assay, cell-based endosome enlargement assay, domain deletion analysis The Journal of biological chemistry High 15247254
2004 AlsinLF (ALS2 long form) activates Rac1 via its Rho GEF (DH/PH) domain, increasing GTP-loaded Rac1 levels, and this Rac1 activation mediates neuroprotection against mutant SOD1-induced motor neuron cell death through a PI3K/Akt3 anti-apoptotic pathway. Rac1 physically associates with AlsinLF and is required for its neuroprotective activity as shown by siRNA knockdown. Co-immunoprecipitation, GTP-Rac1 pull-down assay, siRNA knockdown of Rac1, overexpression of constitutively active Rac1, cell viability assay in NSC34 motoneuronal cells The Journal of biological chemistry High 15579468
2004 AlsinLF binds to mutant SOD1 (but not wild-type SOD1) via its RhoGEF domain, and this interaction is required for alsin-mediated neuroprotection against mutant SOD1 toxicity in motor neuronal cells. Co-immunoprecipitation, deletion analysis of alsin domains, cell viability assay The Journal of biological chemistry Medium 14970233
2005 ALS2 stimulates Rac1 (but not Rho or Cdc42) GTPase activity via its DH/PH domain and induces a corresponding increase in PAK1 kinase activity; ALS2 is present in neuronal growth cones where it co-localizes with Rac1 and promotes neurite outgrowth. GTPase activation assays (Rac1, Rho, Cdc42 pull-down), PAK1 kinase assay, immunofluorescence co-localization in growth cones, neurite outgrowth assay The Journal of biological chemistry High 16049005
2005 Als2-null mice show significantly smaller-sized EGF-positive endosomes in fibroblasts (quantitative EGF-uptake analysis) and age-dependent, slowly progressive loss of cerebellar Purkinje cells and disturbance of spinal motor neurons with astrocytosis and microglial activation, establishing ALS2's role in endosome/vesicle trafficking in vivo. Gene-targeted knockout mice, quantitative EGF-uptake analysis, immunohistochemistry, electrophysiology Human molecular genetics High 16321985
2006 Brain cytosol from Als2(-/-) mice shows marked diminution of Rab5-dependent endosome fusion activity; primary neurons from Als2(-/-) mice show disturbed endosomal transport of IGF1 and BDNF receptors, while transferrin and dextran endocytosis remain intact. Als2(-/-) mice are mildly hypoactive with a significant decrease in cortical motor neuron size. Rab5-dependent endosome fusion assay in brain cytosol, live-cell trafficking of fluorescently labeled receptor ligands in primary neurons, behavioral analysis, histology Proceedings of the National Academy of Sciences of the United States of America High 16769894
2006 ALS2-deficient mice demonstrate progressive axonal degeneration in the lateral spinal cord (upper motor neuron pathology) with preserved lower motor neurons, and exhibit slowed movement consistent with upper motor neuron defects, establishing ALS2 deficiency as causing upper motor neuron disease resembling hereditary spastic paralysis. Gene-targeted ALS2-knockout mice, neuropathological examination, behavioral motor testing Annals of neurology High 16802286
2006 The first ALS2 missense mutation (p.G540E) within the RCC1 domain causes complete loss of alsin's subcellular co-localization with EEA1 and enlarged endosomal structures, indicating protein delocalization. Mutant alsin induces neuronal death and enhances NMDA/staurosporine apoptosis via decreased Bcl-xL:Bax ratio, while wild-type alsin is neuroprotective and increases this ratio. Immunofluorescence co-localization in SK-N-BE neuronal cells, cell viability assay, Western blot for Bcl-xL/Bax Brain : a journal of neurology Medium 16670179
2007 ALS2 preferentially interacts with activated (GTP-loaded) Rac1; activated Rac1 recruits cytoplasmic ALS2 to membrane ruffles and subsequently to nascent macropinosomes via Rac1-activated macropinocytosis. ALS2 then promotes fusion of macropinosomes with transferrin-positive endosomes in a Rab5 GEF activity-dependent manner, establishing ALS2 as a Rac1 effector in macropinocytosis. Co-immunoprecipitation with GTP/GDP-loaded Rac1, live-cell imaging of macropinosome dynamics, GEF-activity-deficient mutant rescue experiments The Journal of biological chemistry High 17409386
2007 ALS2CL (ALS2 C-terminal like) forms homo-dimers that interact with ALS2 oligomers to form large ALS2/ALS2CL heteromeric complexes; overexpressed ALS2CL co-localizes with ALS2 on membranous compartments and dominantly suppresses ALS2-induced endosome enlargement, producing a perinuclear tubulo-membranous phenotype in a manner dependent on ALS2CL-ALS2 interaction. Co-immunoprecipitation, co-localization by immunofluorescence, dominant-negative functional assay in HeLa cells Biochemical and biophysical research communications Medium 17239822
2008 ALS2 deficiency in primary cultured neurons results in delayed axon outgrowth in hippocampal neurons and decreased fluid-phase horseradish peroxidase uptake (macropinocytic endocytosis) in cortical neurons, demonstrating ALS2's role as a modulator of neuronal differentiation and macropinocytosis. Primary neuronal cultures from Als2-KO mice, axon outgrowth measurement, HRP fluid-phase uptake assay Biochemical and biophysical research communications Medium 18358238
2009 Alsin-depleted spinal motor neurons can be rescued from defective survival and axon growth by co-cultured astrocytes via a soluble protective factor (not cell contact), while cortical neurons cannot be rescued, demonstrating non-cell-autonomous glial neuroprotection that may explain the selective vulnerability of upper motor neurons in ALS2-linked disease. Alsin shRNA knockdown in primary neurons, co-culture with astrocytes, cell survival and axon growth assays, conditioned medium experiments Human molecular genetics Medium 19304783
2010 ALS2 co-localizes with LC3 and p62 on autophagosome/endosome hybrid compartments (amphisomes); loss of ALS2 significantly lowers lysosome-dependent clearance of LC3 and p62 in cultured cells and exacerbates SOD1(H46R)-mediated disease in mice by disturbing endolysosomal trafficking and increasing accumulation of insoluble high-molecular-weight SOD1 and poly-ubiquitinated proteins. Co-localization immunofluorescence, lysosomal clearance assay (LC3/p62 turnover), ALS2/SOD1 double-knockout mouse genetic epistasis, biochemical fractionation, electron microscopy PloS one High 20339559
2011 Pathogenic missense ALS2 mutants fail to relocalize to Rac1-induced macropinosomes and endosomes, losing Rab5 GEF activity on endosomes. These mutants also lose the ability to enhance amphisome formation (autophagosome-endosome fusion), linking defective Rac1-stimulated relocalization to disruption of the autophagy-endolysosomal degradative pathway. Live-cell imaging of Rac1-induced macropinocytosis, Rab5 GEF activity assay, amphisome formation assay with pathogenic missense mutants FEBS letters Medium 21300063
2011 ALS2 physically interacts with UXT (Ubiquitously Expressed Transcript), an α-class prefoldin chaperone, confirmed by yeast two-hybrid and co-immunoprecipitation; both proteins co-localize in the cytoplasm of Neuro2a neuronal cells, and their transcription levels change synchronously with cell cycle arrest. Yeast two-hybrid screen, co-immunoprecipitation, immunofluorescence co-localization, transcriptional analysis Biochemical and biophysical research communications Low 21907703
2018 Pathogenic missense ALS2 variants show altered oligomeric states: RLD and PH domain mutations shift ALS2 toward higher molecular weight complexes while a VPS9 domain missense mutant forms smaller dimers/trimers compared to the wild-type tetramer. All mutants move to membrane ruffles upon Rac1 activation but fail to traffic to macropinosomes/endosomes. In silico mutagenesis of the RLD structure and cycloheximide chase assay show these mutations decrease protein stability. Gel-filtration chromatography, live-cell imaging upon Rac1 activation, cycloheximide chase assay, in silico structural mutagenesis using RLD crystal structure The Journal of biological chemistry High 30224357
2020 ALS2 interacts with Rab17 (but does not act as a GEF for Rab17) and acts downstream of RABGEF1 to regulate maturation of Rab17-residing nascent endosomes (arising via clathrin-independent endocytosis) to EEA1-positive early endosomes in a Rac1-dependent manner. Co-immunoprecipitation, GEF assay for Rab17, immunofluorescence co-localization, Rac1 activation experiments, dominant-negative Rab11 epistasis Biochemical and biophysical research communications Medium 31959474
2020 Hypoxia upregulates ALS2 expression via HIF-1α-dependent transcription (functional HIF-1α-binding site identified in the ALS2 proximal promoter by ChIP and bioinformatics), and ALS2 is required for Rab5 activation, tumor cell migration, invasion, and experimental metastasis in hypoxic conditions. RNAi knockdown, pharmacological HIF-1α inhibition, chromatin immunoprecipitation, GTP-Rab5 pull-down assay, cell migration/invasion assays, in vivo metastasis assay in C57BL/6 mice Scientific reports Medium 33339852
2021 Drosophila ALS2 (dALS2) promotes postsynaptic development by activating the Frizzled nuclear import (FNI) pathway; dALS2 loss causes structural defects in the postsynaptic subsynaptic reticulum rescued by postsynaptic expression of the signaling-competent C-terminal fragment of Frizzled-2. dALS2 directs early-to-late endosome trafficking and the dFz2 C terminus is cleaved in late endosomes. dALS2 loss also causes age-dependent locomotor impairment and brain neurodegeneration independently of the FNI pathway. Drosophila genetic loss-of-function, rescue with Frizzled-2 C-terminal fragment, live imaging of endosomal trafficking, confocal imaging of postsynaptic reticulum The Journal of cell biology High 33683284
2021 The intrinsically disordered region (IDR) within the RLD of ALS2 is required for proper intracellular localization and self-oligomerization; IDR-deleted ALS2 accumulates in perinuclear aggregates co-localizing with SQSTM1 and forms an abnormally high molecular weight complex. Phosphorylation at Ser483, Ser492 or Thr510 within the IDR does not significantly affect these properties. Transfection of IDR-deletion and phospho-mimetic mutants in HeLa cells, immunofluorescence co-localization, gel-filtration chromatography for complex size determination Biochemical and biophysical research communications Medium 34243065
2022 In the central nervous system, ALS2 is enriched in both synaptosomal and cytosolic fractions (while liver ALS2 is almost exclusively cytosolic); cytosolic brain ALS2 forms a tetramer by gel filtration, and synaptosomal ALS2 additionally forms a CNS-specific high-molecular-weight homophilic oligomeric complex not observed in fibroblasts. Differential centrifugation subcellular fractionation of brain tissue, gel-filtration chromatography, comparison across cell types and tissues Biochemical and biophysical research communications Medium 36459881
2024 Hypoxia promotes ALS2 incorporation as cargo into small extracellular vesicles from tumor cells; these vesicles transfer ALS2 to recipient endothelial cells where it activates Rab5, increases early endosome size/number, sequesters β-catenin destruction complex components in endosomes, and stabilizes/nuclear-localizes β-catenin to drive pro-angiogenic gene expression. Knockdown of ALS2 in donor cells prevents all downstream endothelial responses. ALS2 knockdown in donor tumor cells, small extracellular vesicle isolation, GTP-Rab5 pull-down assay, β-catenin localization and target gene expression, tube formation and migration assays FASEB journal Medium 38847490
2016 ALS2 and SQSTM1/p62 have distinct but additive protective roles in mutant SOD1-mediated ALS; double knockout (Sqstm1/Als2) in SOD1(H46R) mice further accelerates disease onset compared to single knockouts. ALS2 loss enhances accumulation of insoluble poly-ubiquitinated proteins while SQSTM1 loss promotes selective ubiquitin-positive aggregate accumulation in neurons, implicating both in modulating proteostasis through the autophagy-endolysosomal system. Triple transgenic mouse genetics (SOD1(H46R) × Sqstm1-null × Als2-null), biochemical fractionation for insoluble protein, histopathology, behavioral assessment Human molecular genetics High 27439389
2008 Neurocalcin alpha (NCalpha) co-precipitates with alsin (ALS2) in an immunoprecipitation from brain tissue, and alsin associates with neuronal membrane microdomains (lipid rafts) in a Ca²⁺-dependent manner mediated through NCalpha; Ca²⁺ loading increases membrane association of both proteins in cultured neurons. Immunoprecipitation from brain lysate detected by LC-MS/MS and confirmed by specific antibody, membrane microdomain fractionation, Ca²⁺ chelation/loading experiments, immunostaining of cultured neurons Neuroscience letters Low 18482800

Source papers

Stage 0 corpus · 74 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 ALS2, a novel guanine nucleotide exchange factor for the small GTPase Rab5, is implicated in endosomal dynamics. Human molecular genetics 202 12837691
2005 Mice deficient in the Rab5 guanine nucleotide exchange factor ALS2/alsin exhibit age-dependent neurological deficits and altered endosome trafficking. Human molecular genetics 111 16321985
2006 Als2-deficient mice exhibit disturbances in endosome trafficking associated with motor behavioral abnormalities. Proceedings of the National Academy of Sciences of the United States of America 110 16769894
2005 Loss of ALS2 function is insufficient to trigger motor neuron degeneration in knock-out mice but predisposes neurons to oxidative stress. The Journal of neuroscience : the official journal of the Society for Neuroscience 102 16107644
2010 Loss of ALS2/Alsin exacerbates motor dysfunction in a SOD1-expressing mouse ALS model by disturbing endolysosomal trafficking. PloS one 90 20339559
2004 A Rac1/phosphatidylinositol 3-kinase/Akt3 anti-apoptotic pathway, triggered by AlsinLF, the product of the ALS2 gene, antagonizes Cu/Zn-superoxide dismutase (SOD1) mutant-induced motoneuronal cell death. The Journal of biological chemistry 85 15579468
1998 Identification of Candida albicans ALS2 and ALS4 and localization of als proteins to the fungal cell surface. Journal of bacteriology 84 9765564
2006 The first ALS2 missense mutation associated with JPLS reveals new aspects of alsin biological function. Brain : a journal of neurology 81 16670179
2004 Alsin, the product of ALS2 gene, suppresses SOD1 mutant neurotoxicity through RhoGEF domain by interacting with SOD1 mutants. The Journal of biological chemistry 75 14970233
2003 Unstable mutants in the peripheral endosomal membrane component ALS2 cause early-onset motor neuron disease. Proceedings of the National Academy of Sciences of the United States of America 71 14668431
2005 ALS2/Alsin regulates Rac-PAK signaling and neurite outgrowth. The Journal of biological chemistry 70 16049005
2007 The Rab5 activator ALS2/alsin acts as a novel Rac1 effector through Rac1-activated endocytosis. The Journal of biological chemistry 69 17409386
2007 Molecular and cellular function of ALS2/alsin: implication of membrane dynamics in neuronal development and degeneration. Neurochemistry international 69 17566607
2004 Homo-oligomerization of ALS2 through its unique carboxyl-terminal regions is essential for the ALS2-associated Rab5 guanine nucleotide exchange activity and its regulatory function on endosome trafficking. The Journal of biological chemistry 59 15247254
2006 Progressive spinal axonal degeneration and slowness in ALS2-deficient mice. Annals of neurology 56 16802286
2016 Functional links between SQSTM1 and ALS2 in the pathogenesis of ALS: cumulative impact on the protection against mutant SOD1-mediated motor dysfunction in mice. Human molecular genetics 49 27439389
2006 Novel missense mutation in ALS2 gene results in infantile ascending hereditary spastic paralysis. Annals of neurology 45 16718699
2005 Novel mutation in the ALS2 gene in juvenile amyotrophic lateral sclerosis. Annals of neurology 45 16240357
2011 Defective relocalization of ALS2/alsin missense mutants to Rac1-induced macropinosomes accounts for loss of their cellular function and leads to disturbed amphisome formation. FEBS letters 42 21300063
2001 Cloning and characterization of three novel genes, ALS2CR1, ALS2CR2, and ALS2CR3, in the juvenile amyotrophic lateral sclerosis (ALS2) critical region at chromosome 2q33-q34: candidate genes for ALS2. Genomics 41 11161814
2008 Als2 mRNA splicing variants detected in KO mice rescue severe motor dysfunction phenotype in Als2 knock-down zebrafish. Human molecular genetics 37 18558633
2008 ALS2/alsin deficiency in neurons leads to mild defects in macropinocytosis and axonal growth. Biochemical and biophysical research communications 36 18358238
2004 ALS2CL, the novel protein highly homologous to the carboxy-terminal half of ALS2, binds to Rab5 and modulates endosome dynamics. FEBS letters 36 15388334
2003 Mutation screening of the ALS2 gene in sporadic and familial amyotrophic lateral sclerosis. Archives of neurology 34 14676054
2018 Altered oligomeric states in pathogenic ALS2 variants associated with juvenile motor neuron diseases cause loss of ALS2-mediated endosomal function. The Journal of biological chemistry 31 30224357
2008 ALS2/alsin knockout mice and motor neuron diseases. Neuro-degenerative diseases 30 18714162
2009 A novel ALS2 splice-site mutation in a Cypriot juvenile-onset primary lateral sclerosis family. Neurology 28 19122027
2008 Novel homozygous ALS2 nonsense mutation (p.Gln715X) in sibs with infantile-onset ascending spastic paralysis: the first cases from northwestern Europe. European journal of human genetics : EJHG 26 18523452
2014 ALS2 mutations: juvenile amyotrophic lateral sclerosis and generalized dystonia. Neurology 25 24562058
2008 Maternal uniparental heterodisomy with partial isodisomy of a chromosome 2 carrying a splice acceptor site mutation (IVS9-2A>T) in ALS2 causes infantile-onset ascending spastic paralysis (IAHSP). Neurogenetics 25 18810511
2014 Molecular and phenotypic characterization of Als1 and Als2 mutations conferring tolerance to acetolactate synthase herbicides in soybean. Pest management science 24 24425499
2005 Cross-species characterization of the ALS2 gene and analysis of its pattern of expression in development and adulthood. Neurobiology of disease 24 15686953
2018 Clinical presentation and natural history of infantile-onset ascending spastic paralysis from three families with an ALS2 founder variant. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 23 30128655
2013 Infantile-onset ascending hereditary spastic paraplegia with bulbar involvement due to the novel ALS2 mutation c.2761C>T. Gene 23 24315819
2007 ALS2CL, a novel ALS2-interactor, modulates ALS2-mediated endosome dynamics. Biochemical and biophysical research communications 23 17239822
1998 Refined mapping and characterization of the recessive familial amyotrophic lateral sclerosis locus (ALS2) on chromosome 2q33. Neurogenetics 22 9933298
2020 Genotype-phenotype correlation in seven motor neuron disease families with novel ALS2 mutations. American journal of medical genetics. Part A 21 33155358
2022 ALS2-Related Motor Neuron Diseases: From Symptoms to Molecules. Biology 20 35053075
1995 Identification of the candidate ALS2 gene at chromosome 2q33 as a human aldehyde oxidase gene. Redox report : communications in free radical research 20 27405828
1997 Molecular cloning, refined chromosomal mapping and structural analysis of the human gene encoding aldehyde oxidase (AOX1), a candidate for the ALS2 gene. Redox report : communications in free radical research 19 27406959
2014 A novel splice-site mutation in ALS2 establishes the diagnosis of juvenile amyotrophic lateral sclerosis in a family with early onset anarthria and generalized dystonias. PloS one 17 25474699
1999 A yeast artificial chromosome-based physical map of the juvenile amyotrophic lateral sclerosis (ALS2) critical region on human chromosome 2q33-q34. Genomics 17 9889004
2009 Astrocytic protection of spinal motor neurons but not cortical neurons against loss of Als2/alsin function. Human molecular genetics 16 19304783
2014 A novel homozygous mutation in ALS2 gene in four siblings with infantile-onset ascending hereditary spastic paralysis. European journal of medical genetics 13 24704789
2018 KIF5A and ALS2 Variants in a Family With Hereditary Spastic Paraplegia and Amyotrophic Lateral Sclerosis. Frontiers in neurology 12 30581417
2016 Identification of two novel ALS2 mutations in infantile-onset ascending hereditary spastic paraplegia. Amyotrophic lateral sclerosis & frontotemporal degeneration 12 26751646
2021 ALS2 regulates endosomal trafficking, postsynaptic development, and neuronal survival. The Journal of cell biology 11 33683284
2010 Genetic background and gender effects on gross phenotypes in congenic lines of ALS2/alsin-deficient mice. Neuroscience research 11 20558214
2017 A novel mutation in ALS2 associated with severe and progressive infantile onset of spastic paralysis. Journal of neurogenetics 10 28502191
2011 Alfa-class prefoldin protein UXT is a novel interacting partner of Amyotrophic Lateral Sclerosis 2 (Als2) protein. Biochemical and biophysical research communications 10 21907703
2024 Tumor-derived hypoxic small extracellular vesicles promote endothelial cell migration and tube formation via ALS2/Rab5/β-catenin signaling. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 8 38847490
2021 The N-terminal intrinsically disordered region mediates intracellular localization and self-oligomerization of ALS2. Biochemical and biophysical research communications 8 34243065
2020 ALS2, the small GTPase Rab17-interacting protein, regulates maturation and sorting of Rab17-associated endosomes. Biochemical and biophysical research communications 7 31959474
2006 Deficiency in the ALS2 gene does not affect the motor neuron degeneration in SOD1(G93A) transgenic mice. Neurobiology of aging 7 16973244
2006 Mice deficient in the ALS2 gene exhibit lymphopenia and abnormal hematopietic function. Journal of neuroimmunology 7 17156857
2003 Single-nucleotide polymorphisms in uncoding regions of ALS2 gene of Japanese patients with autosomal-recessive amyotrophic lateral sclerosis. Neurological research 7 12866199
2022 2-Year-Old and 3-Year-Old Italian ALS Patients with Novel ALS2 Mutations: Identification of Key Metabolites in Their Serum and Plasma. Metabolites 6 35208248
2021 ALS2-related disorders in Spanish children. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 6 33409823
2005 Purification and functional analyses of ALS2 and its homologue. Methods in enzymology 5 16473597
2022 A novel mutation in the ALS2 gene in an iranian kurdish family with juvenile amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis & frontotemporal degeneration 4 35852402
2008 Molecular interaction of neurocalcin alpha with alsin (ALS2). Neuroscience letters 4 18482800
2024 Clinical features and molecular genetic investigation of infantile-onset ascending hereditary spastic paralysis (IAHSP) in two Chinese siblings caused by a novel splice site ALS2 variation. BMC medical genomics 3 38297306
2024 Phenotype and Genotype of Children with ALS2 gene-Related Disorder. Neuropediatrics 3 39424348
2022 Development and validation of monoclonal antibodies specific for Candida albicans Als2, Als9-1, and Als9-2. PloS one 3 35802580
2020 The RabGEF ALS2 is a hypoxia inducible target associated with the acquisition of aggressive traits in tumor cells. Scientific reports 3 33339852
2005 Anti-ALS activity of alsin, the product of the ALS2 gene, and activity-dependent neurotrophic factor. Neuro-degenerative diseases 3 16909018
2023 Clinical and molecular spectrum of a large Egyptian cohort with ALS2-related disorders of infantile-onset of clinical continuum IAHSP/JPLS. Clinical genetics 2 37055917
2022 Central nervous system specific high molecular weight ALS2/alsin homophilic complex is enriched in mouse brain synaptosomes. Biochemical and biophysical research communications 2 36459881
2020 Investigating the expression of ALS2 and ALS9 genes along with allele frequency of ALS9 in patients with vulvovaginal candidiasis. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 2 32084624
2004 A novel somatodendritic marker defined by a peptide derived from the ALS2 protein. Neuroreport 2 15371724
2026 ALS2, encoding a plastid 50 S ribosomal protein L5, is essential for early chloroplast development in rice. Journal of plant research 0 41553447
2025 A novel frameshift variant in ALS2 associated with segmental axonopathy in Merino sheep. Genetics, selection, evolution : GSE 0 41131452
2025 Infantile-Onset Ascending Hereditary Spastic Paraplegia due to a Homozygous ALS2 Exons 24-25 Deletion: Expanding the Genotypic Spectrum. American journal of medical genetics. Part A 0 41294049
2004 [Recessive motor neuron diseases: mutations in the ALS2 gene and molecular pathogenesis for the upper motor neurodegeneration]. Rinsho shinkeigaku = Clinical neurology 0 15651293