Affinage

ALS2

Alsin · UniProt Q96Q42

Length
1657 aa
Mass
183.6 kDa
Annotated
2026-06-09
74 papers in source corpus 24 papers cited in narrative 25 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

ALS2/alsin is a multidomain guanine-nucleotide exchange factor that orchestrates endosomal trafficking and membrane dynamics in neurons by activating small GTPases (PMID:12837691, PMID:16049005). Its C-terminal VPS9 domain catalyzes guanine-nucleotide exchange on Rab5 and directs ALS2 to the cytoplasmic face of early endosomes, where it promotes endosome fusion and enlargement; the N-terminal RCC1-like (RLD) domain governs membrane association and the central DH/PH domain enhances VPS9-mediated fusion (PMID:12837691, PMID:14668431). Rab5 GEF activity requires ALS2 self-assembly into homo-tetramers through its C-terminal regions, and disruption of this oligomeric state abolishes endosome enlargement (PMID:15247254, PMID:30224357). Through its DH/PH domain ALS2 also acts as a GEF for Rac1, and activated GTP-Rac1 reciprocally recruits cytoplasmic ALS2 to membrane ruffles and nascent macropinosomes, establishing ALS2 as both a Rac1 activator and a Rac1 effector that couples macropinocytosis to Rab5-dependent endosome fusion (PMID:15579468, PMID:16049005, PMID:17409386). Downstream of Rac1, ALS2 elevates PAK1 activity and promotes neurite/axon outgrowth, while its endosomal activity supports trafficking of neurotrophic receptors (IGF-1, BDNF), amphisome formation, and lysosome-dependent clearance of LC3 and p62 (PMID:16049005, PMID:16769894, PMID:20339559). Loss of ALS2 in mice alters endosome trafficking and produces age-dependent upper motor neuron axonal degeneration, Purkinje cell loss, and impaired proteostasis, and ALS2 acts additively with SQSTM1/p62 in the autophagy-endolysosomal clearance of mutant SOD1 (PMID:16321985, PMID:16802286, PMID:27439389). Disease-causing missense mutations converge on loss of these endosomal GEF functions through protein instability and failure to traffic to Rac1-induced macropinosomes and endosomes (PMID:21300063, PMID:30224357). Beyond its neuronal role, ALS2 is transcriptionally induced by HIF-1α under hypoxia and, when delivered via extracellular vesicles, drives Rab5- and β-catenin-dependent angiogenic and pro-metastatic signaling (PMID:33339852, PMID:38847490).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2003 High

    Established ALS2's core molecular activity by showing it is a GEF for Rab5 and mapping the domain architecture that controls catalysis and membrane targeting.

    Evidence GEF activity assays, co-localization, and domain deletion in cortical neurons and human cells

    PMID:12837691 PMID:14668431

    Open questions at the time
    • Structural basis of VPS9 catalysis not resolved
    • Whether RLD-mediated suppression of localization is regulated in vivo unknown
  2. 2003 High

    Linked ALS2 loss of function to protein instability, showing endogenous protein binds endosomal membranes via the RLD domain and that disease mutants and the truncated isoform are rapidly degraded.

    Evidence Subcellular fractionation, domain constructs, and stability assays in human and patient-derived cells

    PMID:14668431

    Open questions at the time
    • Degradation pathway for unstable mutants not defined
    • Quantitative contribution of instability vs mislocalization not separated
  3. 2004 High

    Showed homo-oligomerization is mechanistically required for GEF activity, explaining how ALS2 assembles into a functional Rab5 activator.

    Evidence Yeast two-hybrid, in vitro Rab5 GEF reconstitution, and endosome morphology readout

    PMID:15247254

    Open questions at the time
    • Oligomerization interface not structurally mapped
    • Single-lab in vitro reconstitution
  4. 2004 High

    Expanded ALS2's GTPase repertoire to Rac1 and connected this to neuroprotection against mutant SOD1 via PI3K/Akt3 signaling and direct mutant-SOD1 binding.

    Evidence Co-IP, GTP-Rac1 pull-down, siRNA epistasis in NSC34 motoneuronal cells

    PMID:14970233 PMID:15579468

    Open questions at the time
    • Physiological relevance of mutant-SOD1 binding (idx 5 Medium) not validated in vivo
    • Whether Rac1 GEF activity is required for SOD1 neuroprotection not isolated
  5. 2005 High

    Tied ALS2's Rac1 activity to PAK1 signaling and neurite outgrowth, placing ALS2 in growth-cone cytoskeletal regulation.

    Evidence GTPase and PAK1 kinase assays, growth-cone immunostaining, neurite outgrowth measurement

    PMID:16049005

    Open questions at the time
    • Direct PAK1 phosphorylation substrates downstream not identified
    • Selectivity over Rho/Cdc42 mechanism unexplained
  6. 2005 High

    Demonstrated in vivo that ALS2 loss disrupts endosome trafficking and causes selective upper motor neuron axonal degeneration, anchoring the cellular mechanism to disease-relevant pathology.

    Evidence Als2-null mouse histology, EGF-uptake endosome quantitation, behavioral and electrophysiological phenotyping

    PMID:16321985 PMID:16802286

    Open questions at the time
    • Mechanism of selective upper motor neuron vulnerability unexplained
    • Relationship between endosome defect and neurodegeneration not causally dissected
  7. 2006 High

    Reconstituted the trafficking defect biochemically, showing Als2-null brain cytosol has reduced Rab5-dependent endosome fusion and that neurotrophic (IGF-1, BDNF) receptor transport is selectively impaired.

    Evidence In vitro endosome fusion assay and live-cell receptor trafficking in KO primary neurons

    PMID:16769894

    Open questions at the time
    • Why transferrin/dextran endocytosis is spared not explained
    • Direct cargo selectivity mechanism unknown
  8. 2007 High

    Resolved the recruitment logic by showing ALS2 binds activated Rac1 and is recruited to ruffles and macropinosomes, where its Rab5 GEF activity drives macropinosome-endosome fusion — defining ALS2 as a Rac1 effector.

    Evidence Nucleotide-state-selective Co-IP, live imaging, and Rab5 GEF assays with CA/DN Rac1

    PMID:17409386

    Open questions at the time
    • How Rac1-driven and Rac1-activating roles are temporally coordinated unclear
    • Structural basis of Rac1-GTP recognition not defined
  9. 2008 Medium

    Confirmed ALS2's role in neuronal differentiation and membrane dynamics through KO loss of axon outgrowth and macropinocytic uptake.

    Evidence Axon outgrowth and HRP fluid-phase uptake assays in Als2 KO primary neurons

    PMID:18358238

    Open questions at the time
    • Single-lab phenotype
    • Link between macropinocytosis defect and outgrowth not mechanistically connected
  10. 2010 High

    Extended ALS2 function to autophagy, showing it localizes to amphisomes and supports lysosomal clearance of LC3/p62 and clearance of insoluble mutant SOD1.

    Evidence Co-localization, lysosome-inhibitor clearance assays, insoluble-fraction blots, EM in SOD1(H46R) double-mutant mice

    PMID:20339559

    Open questions at the time
    • Whether amphisome formation requires Rab5 GEF activity not directly tested here
    • Molecular step ALS2 acts at in amphisome biogenesis undefined
  11. 2011 Medium

    Unified the disease mechanism by showing pathogenic missense mutants fail to relocalize to Rac1-induced macropinosomes/endosomes and lose both Rab5 activation and amphisome-enhancing function.

    Evidence Pathogenic mutant expression with CA-Rac1, Rab5 GEF assay, LC3/endosome co-localization

    PMID:21300063

    Open questions at the time
    • Single-lab mutant analysis
    • Not all clinical mutations tested
  12. 2018 High

    Defined the native tetrameric state and showed all missense mutants destabilize the protein and disrupt its oligomeric assembly and trafficking, providing a structural rationale for loss of function.

    Evidence Gel filtration, cycloheximide chase, in silico RLD mutagenesis, CA-Rac1 localization

    PMID:30224357

    Open questions at the time
    • High-resolution structure of full-length tetramer lacking
    • How destabilization causes mistrafficking despite reaching ruffles unclear
  13. 2021 Medium

    Identified the RLD intrinsically disordered region as essential for localization and self-oligomerization, with candidate IDR phosphosites being dispensable.

    Evidence IDR-deletion and phosphomimetic mutants in HeLa, gel filtration, SQSTM1 co-localization

    PMID:34243065

    Open questions at the time
    • Functional regulator of the IDR not identified
    • Single-lab, heterologous (HeLa) system
  14. 2020 Medium

    Broadened the Rab repertoire and pathway position by showing ALS2 binds Rab17 (without being its GEF) and acts downstream of RABGEF1 to mature Rab17/clathrin-independent endosomes to EEA1-positive endosomes.

    Evidence Co-IP, negative Rab17 GEF assay, RABGEF1/Rab11 epistasis, CA/DN constructs, co-localization

    PMID:31959474

    Open questions at the time
    • Functional consequence of Rab17 binding in neurons untested
    • Single-lab study
  15. 2021 High

    Provided cross-species developmental context, showing Drosophila ALS2 drives postsynaptic development via Frizzled nuclear import through endosome maturation, plus an FNI-independent neurodegeneration role.

    Evidence Drosophila KO/rescue genetics, NMJ/SSR immunostaining, FNI epistasis, endosomal live imaging, aged locomotor assays

    PMID:33683284

    Open questions at the time
    • Whether mammalian ALS2 engages Frizzled/Wnt signaling not shown
    • Mechanism of FNI-independent neurodegeneration unknown
  16. 2022 Medium

    Characterized tissue-specific assembly, showing cytosolic ALS2 is tetrameric in brain and liver but synaptosomal ALS2 forms a CNS-specific high-molecular-weight complex.

    Evidence Subcellular fractionation and gel filtration across brain, liver, neuronal, glial, and fibroblast lysates

    PMID:36459881

    Open questions at the time
    • Composition of the CNS-specific high-MW complex unknown
    • Functional role of synaptic localization not tested
  17. 2024 Medium

    Revealed a non-neuronal signaling axis whereby hypoxia-induced ALS2 (HIF-1α dependent) is packaged into extracellular vesicles and drives Rab5- and β-catenin-dependent angiogenesis and metastasis.

    Evidence ChIP, Rab5-GTP pull-down, sEV transfer, β-catenin signaling, tube formation and metastasis assays

    PMID:33339852 PMID:38847490

    Open questions at the time
    • Mechanism of ALS2 sorting into sEVs unknown
    • Single-lab cancer findings; relevance to neuronal disease unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ALS2's dual GEF activities, tetramerization, and tissue-specific complexes are coordinated at the structural and regulatory level, and why upper motor neurons are selectively vulnerable to ALS2 loss, remains unresolved.
  • No high-resolution structure of the active tetramer or GTPase-bound complexes
  • Selective motor neuron vulnerability mechanism unexplained
  • Physiological signals controlling ALS2 recruitment and oligomerization undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0140096 catalytic activity, acting on a protein 5
Localization
GO:0005768 endosome 5 GO:0005829 cytosol 3 GO:0005886 plasma membrane 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-9612973 Autophagy 2
Partners
NCALDRAB17RAB5RABGEF1RAC1SOD1SQSTM1UXT
Complex memberships
ALS2 homo-tetramer

Evidence

Reading pass · 25 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, which mediates both Rab5 activation through guanine-nucleotide exchange and endosomal localization of the ALS2 protein. The amino-terminal RLD domain acts suppressively on membranous localization, while the central DH/PH domain enhances VPS9-mediated endosome fusions. Co-localization, ectopic expression in cortical neurons, GEF activity assays, domain deletion analysis Human molecular genetics High 12837691
2003 Ectopically expressed ALS2 protein localizes with Rab5 and EEA1 onto early endosomal compartments and stimulates enlargement of endosomes in cultured cortical neurons in a VPS9 domain-dependent manner. Ectopic expression, co-localization with endosomal markers (EEA1, Rab5), morphological analysis in cultured cortical neurons Human molecular genetics High 12837691 14668431
2003 Endogenous ALS2 is peripherally bound to the cytoplasmic face of endosomal membranes, and this association requires the amino-terminal RCC1-like GEF domain. Disease-causing ALS2 mutants and the naturally truncated isoform are rapidly degraded, establishing loss of function through protein instability. Subcellular fractionation, domain deletion constructs, expression in cultured human cells and patient-derived lymphocytes, protein stability assays 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, identified by yeast two-hybrid screen; 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, ectopic expression with endosome morphology readout The Journal of biological chemistry High 15247254
2004 AlsinLF (long form of ALS2) activates Rac1 GTPase via its Rho GEF (DH/PH) domain. Rac1 associates with alsinLF, GTP-loaded Rac1 is increased upon alsinLF overexpression, and the neuroprotective effect of alsinLF against mutant SOD1 toxicity is completely abolished by siRNA knockdown of Rac1. The neuroprotective signal is transmitted through PI3K/Akt3. Co-immunoprecipitation, GTP-Rac1 pull-down assay, siRNA knockdown, cell viability assay in NSC34 motoneuronal cells The Journal of biological chemistry High 15579468
2004 AlsinLF binds to mutant SOD1 proteins (but not wild-type SOD1) via its RhoGEF domain; this physical interaction underlies alsin-mediated neuroprotection against mutant SOD1 toxicity. The RhoGEF domain is essential for neuroprotection as shown by deletion analysis. Co-immunoprecipitation, deletion analysis, cell viability assay The Journal of biological chemistry Medium 14970233
2005 ALS2 stimulates Rac1 (but not Rho or Cdc42) GTPase activity and induces a corresponding increase in PAK1 activity. ALS2 is present within growth cones of neurons where it co-localizes with Rac1, and ALS2 promotes neurite outgrowth. GTPase activation assays (pull-down for GTP-bound Rac1/Rho/Cdc42), PAK1 kinase assay, immunostaining of growth cones, neurite outgrowth measurement The Journal of biological chemistry High 16049005
2005 Loss of ALS2 in knockout mice results in significantly smaller EGF-positive endosomes in fibroblasts, demonstrating alteration of endosome/vesicle trafficking in vivo. Age-dependent loss of cerebellar Purkinje cells and spinal motor neuron disturbance with astrocytosis were observed. Als2-null mouse generation, quantitative EGF-uptake analysis, immunohistochemistry, electrophysiology Human molecular genetics High 16321985
2006 Cytosol from brains of Als2-deficient mice shows marked diminution of Rab5-dependent endosome fusion activity. Primary Als2-null neurons show disturbed endosomal transport of IGF-1 and BDNF receptors, while neuronal viability, transferrin and dextran endocytosis are unaltered. Rab5-dependent endosome fusion assay on brain cytosol, live-cell receptor trafficking assay in primary neurons, Als2 KO mice Proceedings of the National Academy of Sciences of the United States of America High 16769894
2007 ALS2 preferentially interacts with activated (GTP-bound) Rac1. Activated Rac1 recruits cytoplasmic ALS2 to membrane ruffles and subsequently to nascent macropinosomes via Rac1-activated macropinocytosis. At later endocytic stages, macropinosomal ALS2 augments fusion of ALS2-localized macropinosomes with transferrin-positive endosomes in a Rab5 GEF activity-dependent manner. Thus ALS2 acts as a Rac1 effector. Co-immunoprecipitation with GTP/GDP-locked Rac1, live cell imaging, dominant-negative/constitutively active Rac1 expression, Rab5 GEF activity assays The Journal of biological chemistry High 17409386
2006 A missense mutation p.G540E in the RCC1 domain of ALS2 completely abolishes the known endosomal localization of wild-type alsin (co-localization with EEA1 and transferrin receptor in enlarged endosomes), indicating protein delocalization. Mutant alsin induced neuronal death and enhanced apoptosis with decreased Bcl-xL:Bax ratio, while wild-type alsin was neuroprotective and increased Bcl-xL:Bax ratio. Expression of mutant vs WT alsin in SK-N-BE neuronal cells, immunofluorescence co-localization, cell viability assay, western blot of Bcl-xL/Bax Brain : a journal of neurology Medium 16670179
2008 ALS2 deficiency in primary cultured neurons results in delayed axon outgrowth in hippocampal neurons and decreased macropinocytic endocytosis (HRP uptake) in cortical neurons, establishing roles for ALS2 in neuronal differentiation and membrane dynamics. Primary cultured neurons from Als2 KO mice, axon outgrowth measurement, fluid-phase HRP uptake assay Biochemical and biophysical research communications Medium 18358238
2010 ALS2 colocalizes 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 in SOD1(H46R) mice ALS2 deficiency leads to enhanced accumulation of insoluble high molecular weight SOD1, poly-ubiquitinated proteins, and autophagy-associated proteins, with accumulation of autophagosome-like vesicles in spinal axons. Co-localization by immunofluorescence, lysosome inhibitor assay (LC3/p62 clearance), western blot of insoluble protein fractions, electron microscopy of spinal axons in double-mutant mice PloS one High 20339559
2011 Pathogenic ALS2 missense mutants fail to localize to Rac1-induced macropinosomes and endosomes, losing their function as Rab5 activators on endosomes. These mutants also lose the ability to enhance amphisome formation (autophagosome-endosome hybrid organelles), linking Rac1-dependent relocalization to autophagy-endolysosomal degradation. Expression of pathogenic ALS2 missense mutants in cells with constitutively active Rac1, immunofluorescence, Rab5 GEF activity assay, LC3/endosome co-localization FEBS letters Medium 21300063
2018 Wild-type ALS2 complexes exist predominantly as tetramers in cells. Pathogenic ALS2 missense mutations in the N-terminal RLD shift the complex toward higher molecular weights, while a C-terminal VPS9 domain missense mutant forms smaller dimeric/trimeric complexes. All missense mutants fail to traffic to macropinosomes/endosomes upon Rac1 activation despite reaching membrane ruffles. In silico mutagenesis and cycloheximide chase assays demonstrate decreased protein stability of missense mutants. Gel filtration chromatography, ectopic expression with constitutively active Rac1, immunofluorescence, cycloheximide chase assay, in silico mutagenesis using RLD crystal structure The Journal of biological chemistry High 30224357
2005 ALS2-deficient mice exhibit progressive axonal degeneration in the lateral spinal cord and slowed movement without muscle weakness, consistent with upper motor neuron dysfunction. Lower motor neurons are preserved, indicating selective vulnerability of upper motor neuron axons. Gene targeting KO mice, histological examination of spinal cord, behavioral motor function tests Annals of neurology High 16802286
2011 UXT (ubiquitously expressed transcript), an alpha-class prefoldin chaperone, is a novel binding partner of ALS2, identified by yeast two-hybrid screen and confirmed by co-immunoprecipitation. ALS2 and UXT co-localize in the cytoplasm of neuronal Neuro2a cells, and their transcript levels change synchronously during cell cycle arrest. Yeast two-hybrid screen, co-immunoprecipitation, immunofluorescence co-localization, RT-PCR during cell cycle arrest Biochemical and biophysical research communications Low 21907703
2008 Neurocalcin alpha (NCalpha), a neuronal calcium sensor protein, co-immunoprecipitates with ALS2/alsin in brain. ALS2 binds to brain-derived membrane microdomain fractions in a Ca2+-dependent manner, mediated through NCalpha, and this membrane association is increased by Ca2+ loading with maitotoxin in cultured neurons. Co-immunoprecipitation (LC-MS/MS identification, antibody-based confirmation), membrane fractionation with Ca2+ chelation, immunostaining with Ca2+ loading Neuroscience letters Low 18482800
2020 ALS2 interacts with Rab17 physically but does not function as a GEF for Rab17 (in contrast to RABGEF1). ALS2 acts downstream of RABGEF1 to regulate maturation of Rab17-residing nascent endosomes (arising via clathrin-independent endocytosis) to EEA1-positive early endosomes. Upon Rac1 activation, Rab17 co-localizes with ALS2 at membrane ruffles and early endosomes in a Rab5-independent manner. Co-immunoprecipitation, GEF activity assay for Rab17, dominant-negative/constitutively active constructs, immunofluorescence co-localization, epistasis via RABGEF1 and Rab11 knockdown Biochemical and biophysical research communications Medium 31959474
2021 Drosophila ALS2 (dALS2) promotes postsynaptic development by activating the Frizzled nuclear import (FNI) pathway; dALS2 loss causes structural defects in the subsynaptic reticulum rescued by postsynaptic expression of the C-terminal fragment of dFz2. 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 genetics (KO and rescue), immunostaining of NMJ/SSR, epistasis with FNI pathway mutants, live imaging of endosomal trafficking, aged fly locomotor assays The Journal of cell biology High 33683284
2021 The intrinsically disordered region (IDR) within the RLD of ALS2 is essential for proper intracellular localization and self-oligomerization. IDR-deleted ALS2 forms abnormally high molecular weight complexes and accumulates in perinuclear aggregates co-localizing with SQSTM1/p62, rather than at endosomes. Phosphorylation of Ser483, Ser492, or Thr510 within the IDR has no detectable effect on localization or oligomeric state. Ectopic expression of IDR-deleted and phospho/dephospho-mimetic ALS2 mutants in HeLa cells, gel filtration chromatography, immunofluorescence co-localization with SQSTM1 Biochemical and biophysical research communications Medium 34243065
2022 In the brain, ALS2 is enriched in synaptosomal and cytosolic fractions (unlike liver where it is almost exclusively cytosolic). Cytosolic ALS2 from both brain and liver exists as a tetramer by gel filtration. Synaptosomal ALS2 additionally forms a high-molecular weight complex specific to CNS (neurons and glia), not found in fibroblast cell lines. Differential centrifugation (subcellular fractionation), gel filtration chromatography of brain/liver/neuronal/glial/fibroblast lysates Biochemical and biophysical research communications Medium 36459881
2020 ALS2 is transcriptionally induced by hypoxia via HIF-1α-dependent transcription; a functional HIF-1α binding site was identified in the proximal ALS2 promoter by chromatin immunoprecipitation. HIF-1α-induced ALS2 upregulation is required for Rab5 activation, tumor cell migration, invasion, and experimental metastasis. RNAi knockdown, pharmacological HIF-1α inhibition, chromatin immunoprecipitation (ChIP), bioinformatics identification of HIF-1α binding site, Rab5-GTP pull-down, migration/invasion assays, in vivo metastasis model Scientific reports Medium 33339852
2024 Hypoxia promotes incorporation of ALS2 as cargo within small extracellular vesicles (sEVs); transferred ALS2 activates Rab5 in recipient endothelial cells, promotes early endosome enlargement, sequesters the β-catenin destruction complex in endosomes, stabilizes and promotes nuclear localization of β-catenin, and activates angiogenic β-catenin target genes. These effects depend on the GEF activity of ALS2. sEV isolation and transfer, Rab5-GTP pull-down, ALS2 knockdown in donor cells, endosome morphology analysis, β-catenin localization/signaling assays, tube formation and migration assays FASEB journal Medium 38847490
2016 ALS2 and SQSTM1/p62 have distinct but additive protective roles against mutant SOD1-mediated toxicity. Simultaneous genetic inactivation of SQSTM1 and ALS2 (double-null on SOD1(H46R) background) accelerated disease onset beyond either single null, and ALS2 loss enhanced accumulation of insoluble poly-ubiquitinated proteins (while SQSTM1 loss preferentially caused ubiquitin-positive aggregates), suggesting they modulate neuronal proteostasis through different aspects of the autophagy-endolysosomal system. Triple transgenic mice (SOD1(H46R) x Sqstm1/Als2 double null), genetic epistasis, biochemical fractionation of insoluble proteins, immunohistochemistry Human molecular genetics Medium 27439389

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 85 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 50 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 Molecular and phenotypic characterization of Als1 and Als2 mutations conferring tolerance to acetolactate synthase herbicides in soybean. Pest management science 25 24425499
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
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
2021 ALS2 regulates endosomal trafficking, postsynaptic development, and neuronal survival. The Journal of cell biology 12 33683284
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
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
2023 Clinical and molecular spectrum of a large Egyptian cohort with ALS2-related disorders of infantile-onset of clinical continuum IAHSP/JPLS. Clinical genetics 3 37055917
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
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 Helicobacter pylori infection activates the HIF-1α/ALS2/Rab5 signaling axis in gastric cells. Cell communication and signaling : CCS 0 42260624
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

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