ALS2 (Alsin)

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ALS2 (Alsin)

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ALS2 (Alsin)

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">ALS2 — Alsin</th>
</tr>
<tr> [@kunita2004]
<td class="label">Symbol</td> [@tudor2010]
<td><strong>ALS2</strong></td> [@kawai2018]
</tr> [@patel2020]
<tr> [@ref]
<td class="label">Full Name</td> [@refa]
<td>Alsin</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>2q33.1</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/5824" target="_blank">5824</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000103307" target="_blank">ENSG00000103307</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/607352" target="_blank">607352</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9Y2H5" target="_blank">Q9Y2H5</a></td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>1,657 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~184 kDa</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[ALS](/diseases/als), Juvenile ALS, Primary Lateral Sclerosis</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Motor cortex, Brainstem, Cerebellum, Spinal cord</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/amyotrophic-lateral-sclerosis" style="color:#ef9a9a">Amyotro

...

ALS2 (Alsin)

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">ALS2 — Alsin</th>
</tr>
<tr> [@kunita2004]
<td class="label">Symbol</td> [@tudor2010]
<td><strong>ALS2</strong></td> [@kawai2018]
</tr> [@patel2020]
<tr> [@ref]
<td class="label">Full Name</td> [@refa]
<td>Alsin</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>2q33.1</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/5824" target="_blank">5824</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000103307" target="_blank">ENSG00000103307</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/607352" target="_blank">607352</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9Y2H5" target="_blank">Q9Y2H5</a></td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>1,657 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~184 kDa</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[ALS](/diseases/als), Juvenile ALS, Primary Lateral Sclerosis</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Motor cortex, Brainstem, Cerebellum, Spinal cord</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/amyotrophic-lateral-sclerosis" style="color:#ef9a9a">Amyotrophic Lateral Sclerosis</a>, <a href="/wiki/dementia" style="color:#ef9a9a">Dementia</a>, <a href="/wiki/frontotemporal-dementia" style="color:#ef9a9a">Frontotemporal Dementia</a>, <a href="/wiki/ftd" style="color:#ef9a9a">Ftd</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">105 edges</a></td>
</tr>
</table>

ALS2 — Alsin

Overview

Mermaid diagram (expand to render)

Als2 (Alsin) plays an important role in the study of neurodegenerative diseases. This page provides comprehensive information about this topic, including its mechanisms, significance in disease processes, and therapeutic implications.

Introduction

ALS2 (Alsin) is a gene located on chromosome 2q33.1 that encodes a critical neuronal protein involved in multiple cellular processes including endosomal trafficking, mitochondrial function, and axonal maintenance. Loss-of-function mutations in ALS2 cause autosomal recessive juvenile-onset forms of amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS), highlighting its essential role in motor neuron survival.

Gene Structure and Expression

The ALS2 gene spans approximately 19.5 kb of genomic DNA and contains 31 exons. It encodes a protein of 1,657 amino acids with a molecular weight of approximately 184 kDa. The gene is expressed predominantly in the central nervous system, with highest expression in motor [neurons](/entities/neurons) of the motor [cortex](/brain-regions/cortex), brainstem (particularly the hypoglossal nucleus), cerebellum, and spinal cord.

Tissue Distribution

Brain: Motor cortex, prefrontal cortex, [hippocampus](/brain-regions/hippocampus), cerebellum
Brainstem: Hypoglossal nucleus, facial nucleus, ambiguus nucleus
Spinal cord: Anterior horn (motor neurons)
Peripheral: Low expression in testis, kidney

Expression is driven by neuronal promoters and is regulated during development, with higher expression in embryonic and early postnatal stages corresponding to periods of active neuronal differentiation and axon guidance.

Protein Structure and Function

Domain Architecture

Alsin contains several functional domains:

RhoGEF domain (N-terminal): Contains the DH (Dbl homology) and PH (Plexstrin homology) domains typical of Rho guanine nucleotide exchange factors (RhoGEFs). This domain catalyzes GDP-to-GTP exchange on small GTPases including Rac1, Cdc42, and Rab5.

VPS9 domain: A conserved domain involved in endosomal trafficking and vacuolar protein sorting. This domain facilitates recruitment of Alsin to early endosomes.

MORN repeat region: Multiple Tryptophan-Serine-Threonine (W-S-T) motif repeats that mediate membrane association, particularly to phospholipid bilayers.

Cysteine-rich domain: Predicted to function in protein-protein interactions.

Molecular Mechanisms

Alsin functions as a multi-functional scaffold protein with several key roles:

Endosomal Trafficking

Alsin acts as a Rab5 effector and regulates endosomal fusion and trafficking through its interactions with early endosomes. The VPS9 domain binds to phosphatidylinositol-3-phosphate (PI3P) on endosomal membranes, targeting Alsin to early endosomes. Through its RhoGEF activity, Alsin activates Rac1 and Cdc42, which orchestrate the actin cytoskeleton remodeling required for endosomal fusion and movement.

This function is critical for:

Retrograde axonal transport of neurotrophic factors
Recycling of neurotransmitter receptors
Membrane protein turnover

Mitochondrial Dynamics

Alsin localizes to mitochondria and regulates mitochondrial fission and fusion dynamics. Mutations in ALS2 lead to fragmented mitochondria with impaired function. Alsin interacts with mitochondrial fission proteins including [Drp1](/proteins/drp1) and regulates its recruitment to mitochondria. Additionally, Alsin helps maintain mitochondrial membrane potential and protects against mitochondrial [apoptosis](/mechanisms/apoptosis).

Axonal Transport and Cytoskeleton

Through its interactions with microtubule motors and actin-binding proteins, Alsin facilitates axonal transport of vesicles, organelles, and signaling complexes. This function is essential for:

Anterograde transport of proteins from cell body to synapse
Retrograde transport of signaling endosomes containing neurotrophins
Maintenance of axonal polarity

Autophagy Regulation

Alsin participates in selective [autophagy](/entities/autophagy) through interactions with autophagy receptors and the autophagosomal machinery. Loss of Alsin function leads to impaired autophagic flux and accumulation of damaged proteins and organelles.

Disease Mechanisms

Homozygous or compound heterozygous mutations in ALS2 cause autosomal recessive neurodegenerative disorders with juvenile onset:

Juvenile ALS (ALS2): Onset between ages 1-20, characterized by progressive spasticity, bulbar dysfunction, and muscle weakness. Typically less severe than adult-onset ALS with slower progression.

Primary Lateral Sclerosis (PLS): Pure upper motor neuron disease with spasticity as the primary symptom. May represent a variant of ALS2 with predominant corticospinal tract involvement.

Infantile-Onset Ascending Spastic Paralysis: Very early onset (before age 2) with progressive spasticity ascending from lower extremities.

Pathogenic Mechanisms

The common pathogenic mechanism involves loss of Alsin function, leading to:

Endosomal dysfunction: Impaired trafficking of neurotrophic factor receptors (TrkA, TrkB, p75NTR) reduces survival signaling to motor neurons.

Mitochondrial failure: Fragmented mitochondria generate excess ROS, have reduced ATP production, and are more prone to releasing cytochrome c during [apoptosis](/entities/apoptosis).

Axonal degeneration: Disrupted axonal transport leads to dying-back neuropathy starting at distal axon terminals, a hallmark of motor neuron disease.

Autophagic-lysosomal impairment: Accumulation of damaged proteins and organelles triggers ER stress and activates apoptosis pathways.

Excitotoxicity susceptibility: Impaired glutamate transporter trafficking may contribute to excitotoxic motor neuron death.

Key Mutations

| Mutation | Type | Effect |
|----------|------|--------|
| Q864X | Nonsense | Truncated protein, loss of VPS9 domain |
| L1004fs | Frameshift | Premature stop, loss of C-terminal domains |
| R1596W | Missense | Impaired mitochondrial targeting |
| IVS1+1G>A | Splicing | Exon skipping, frameshift |

Therapeutic Approaches

Gene Therapy

AAV-mediated ALS2 delivery: Preclinical studies using AAV vectors to deliver functional ALS2 to motor neurons show promise in mouse models.
Antisense oligonucleotides: ASOs targeting pathogenic splice variants or nonsense mutations are in development.

Small Molecule Strategies

Rho GTPase modulators: Compounds that enhance Rac1/Cdc42 activity may compensate for lost Alsin function.
Mitochondrial protectants: CoQ10, idebenone, and other mitochondrial-targeted antioxidants are being tested.
[Autophagy](/mechanisms/autophagy-lysosome-neurodegeneration) enhancers: Rapamycin and related compounds may improve clearance of damaged organelles.

Neurotrophic Factors

BDNF and GDNF delivery: AAV-GDNF and AAV-BDNF have shown protective effects in ALS2 models.
Trk receptor agonists: Small molecule TrkB agonists may enhance survival signaling.

Interactome

Alsin interacts with:

Rho GTPases: Rac1, Cdc42, Rab5
Adaptor proteins: Grb2, Crk
Mitochondrial proteins: [Drp1](/proteins/drp1-protein), OPA1
Trafficking proteins: EEA1, Rabenosyn-5
Cytoskeletal elements: Actin, tubulin
Signaling molecules: PI3K, MAPK pathways

Animal Models

Mouse Models

Als2 knockout mice: Show age-dependent motor deficits, mitochondrial abnormalities, and mild motor neuron degeneration.
Als2 conditional knockout: Motor neuron-specific deletion recapitulates key features of ALS2 disease.
Transgenic ALS2 models: Expressing mutant ALS2 lead to more severe phenotypes.

Zebrafish Models

als2 morphants: Show двигательные deficits and axonal guidance abnormalities.
CRISPR/Cas9 knockouts: Recapitulate juvenile ALS phenotype.

Clinical Features

Symptoms

Progressive muscle weakness (limb onset)
Spasticity (upper motor neuron signs)
Bulbar dysfunction (dysarthria, dysphagia)
Fasciculations and muscle atrophy
Respiratory insufficiency (late stage)

Diagnosis

Genetic testing: Confirm pathogenic ALS2 mutations
Neuroimaging: MRI to rule out other causes
Neurophysiology: EMG shows chronic neurogenic changes
CSF analysis: May show elevated [neurofilament light](/biomarkers/neurofilament-light-chain-nfl) chain

Prognosis

Juvenile ALS with ALS2 mutations typically has slower progression than adult-onset ALS, with survival often into middle age or later.

Research Directions

Understanding genotype-phenotype correlations

Developing high-throughput screens for ALS2 modulators

Biomarker development for disease progression

Combination therapies targeting multiple pathways

Stem cell models derived from ALS2 patients

Overview

Als2 (Alsin) plays an important role in the study of neurodegenerative diseases. This page provides comprehensive information about this topic, including its mechanisms, significance in disease processes, and therapeutic implications.

Background

The study of Als2 (Alsin) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

External Links

[PubMed](https://pubmed.ncbi.nlm.nih.gov/) - Biomedical literature
[Alzheimer's Disease Neuroimaging Initiative](https://adni.loni.usc.edu/) - Research data
[Allen Brain Atlas](https://brain-map.org/) - Brain gene expression data

Brain Atlas Resources

[Allen Human Brain Atlas - ALS2 Expression](https://human.brain-map.org/microarray/search/show?search_term=ALS2)
[Allen Cell Type Atlas - ALS2](https://celltypes.brain-map.org/)
[BrainSpan - ALS2 Developmental Expression](https://brainspan.org/)
[Allen Mouse Brain Atlas - ALS2](https://mouse.brain-map.org/)

References

[Hadano S, et al, (2001) (2001)](https://doi.org/10.1038/414452a)

Cashman NR, et al, (2002) (2002)

Yamanaka K, et al, (2006) (2006)

Otomo A, et al, (2008) (2008)

Kunita R, et al, (2004) (2004)

Tudor EL, et al, (2010) (2010)

Kawai Y, et al, (2018) (2018)

Patel VP, et al, (2020) (2020)

Unknown, (n.d.)

Pathway Diagram

The following diagram shows the key molecular relationships involving ALS2 (Alsin) discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

ALS2

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-als2
kg_node_id	ALS2
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-94e3a8ef64c3
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-als2'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

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Certainty

100%

Debates

0

Incoming

42

Outgoing

41

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

ALS2 (Alsin)

ALS2 (Alsin)

ALS2 (Alsin)

ALS2 — Alsin

Overview

Introduction

Gene Structure and Expression

Tissue Distribution

Protein Structure and Function

Domain Architecture

Molecular Mechanisms

Endosomal Trafficking

Mitochondrial Dynamics

Axonal Transport and Cytoskeleton

Autophagy Regulation

Disease Mechanisms

Pathogenic Mechanisms

Key Mutations

Therapeutic Approaches

Gene Therapy

Small Molecule Strategies

Neurotrophic Factors

Interactome

Animal Models

Mouse Models

Zebrafish Models

Clinical Features

Symptoms

Diagnosis

Prognosis

Research Directions

Overview

Background

See Also

External Links

Brain Atlas Resources

References

Pathway Diagram

💬 Discussion

📗 Cite This Artifact

ALS2 (Alsin)

ALS2 (Alsin)

ALS2 (Alsin)

ALS2 — Alsin

Overview

Introduction

Gene Structure and Expression

Tissue Distribution

Protein Structure and Function

Domain Architecture

Molecular Mechanisms

Endosomal Trafficking

Mitochondrial Dynamics

Axonal Transport and Cytoskeleton

Autophagy Regulation

Disease Mechanisms

ALS2-Related Disorders

Pathogenic Mechanisms

Key Mutations

Therapeutic Approaches

Gene Therapy

Small Molecule Strategies

Neurotrophic Factors

Interactome

Animal Models

Mouse Models

Zebrafish Models

Clinical Features

Symptoms

Diagnosis

Prognosis

Research Directions

Overview

Background

See Also

External Links

Brain Atlas Resources

References

Pathway Diagram

💬 Discussion