ALS8 - Amyotrophic Lateral Sclerosis 8
Overview
Mermaid diagram (expand to render)
<table class="infobox infobox-gene">
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<th class="infobox-header" colspan="2">ALS8 - Amyotrophic Lateral Sclerosis 8</th>
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<td class="label">Symbol</td>
<td>VAPB</td>
</tr>
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<td class="label">Gene Name</td>
<td>Vesicle-Associated Membrane Protein-Associated Protein B</td>
</tr>
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<td class="label">Alias</td>
<td>VAP-B, VAMP-Associated Protein B</td>
</tr>
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<td class="label">Chromosome</td>
<td>20q13.33</td>
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<td class="label">Base Pair Position</td>
<td>62,234,129-62,285,331 (GRCh38)</td>
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<td class="label">OMIM</td>
<td>607348</td>
</tr>
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<td class="label">Ensembl</td>
<td>ENSG00000124194</td>
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<td class="label">UniProt</td>
<td>Q9UBS4</td>
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<td class="label">Protein Type</td>
<td>Type III ER membrane protein</td>
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<td class="label">Length</td>
<td>243 amino acids</td>
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<td class="label">Expression</td>
<td>Ubiquitous, high in brain and spinal cord</td>
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<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/glaucoma" style="color:#ef9a9a">Glaucoma</a></td>
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<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">20 edges</a></td>
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</table>
ALS8 (Amyotrophic Lateral Sclerosis 8) is a genetic locus associated with familial amyotrophic lateral sclerosis (ALS). This form of ALS was first described in a large Brazilian family with a unique constellation of symptoms including ALS and mild cerebellar ataxia. For more information about ALS, see the main [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis) page.
ALS8 is caused by mutations in the VAPB gene (Vesicle-Associated Membrane Protein-Associated Protein B), located at chromosome 20q13.33 [@online]. VAPB is a highly conserved Type III ER membrane protein involved in multiple cellular processes including endoplasmic reticulum (ER) homeostasis, lipid metabolism, calcium signaling, and protein quality control. The identification of VAPB mutations as a cause of ALS provided important insights into the role of ER dysfunction in neurodegenerative diseases.
Protein Structure and Function
VAPB is a 243 amino acid ER-resident protein that plays critical roles in maintaining cellular homeostasis. The protein contains three main structural domains:
Domain Architecture
- N-terminal MSP Domain (1-150 aa): The Major Sperm Protein (MSP) domain is the largest structural region and mediates interactions with FFAT motif-containing proteins. This domain extends into the cytosol and serves as a platform for protein-protein interactions involved in lipid metabolism, ER dynamics, and signaling pathways.
- Coiled-coil Domain (150-200 aa): This region mediates homodimerization and heterodimerization with other VAP family proteins (VAPA, VAPB). Dimerization is essential for proper function and subcellular localization.
- C-terminal Transmembrane Domain (200-243 aa): A single-pass transmembrane helix anchors the protein to the ER membrane with the N-terminus facing the cytosol.
Cellular Functions
VAPB participates in several critical cellular processes:
ER Morphology and Contact Sites: VAPB is a key component of membrane contact sites between the ER and other organelles, particularly mitochondria. These contact sites facilitate inter-organelle communication and lipid transfer [@gauth2015].
Lipid Metabolism: VAPB regulates phospholipid synthesis, lipid droplet formation, and trafficking. It interacts with lipid transfer proteins and coordinates lipid homeostasis between the ER and plasma membrane.
ER-Mitochondrial Calcium Signaling: Through ER-mitochondria contact sites, VAPB influences mitochondrial calcium uptake and cellular calcium dynamics [@kirby2021].
Protein Quality Control: VAPB participates in ER-associated degradation (ERAD) pathways, helping to clear misfolded proteins from the ER lumen.
Autophagy Regulation: VAPB interacts with autophagy machinery and regulates autophagosome formation, linking ER function to cellular clearance mechanisms.Disease Mechanism
The P56S Founder Mutation
The P56S mutation (c.166C>T, p.Pro56Ser) in VAPB was first identified in a large Brazilian family with ALS8 [@nishimura2004]. This mutation represents a founder mutation traced to a common ancestor and is the most prevalent VAPB pathogenic variant. The P56S mutation is located in the N-terminal MSP domain, disrupting multiple protein functions.
Pathogenic Mechanisms
The P56S mutation causes ALS through several interconnected mechanisms [@morelli2019]:
ER Stress and Unfolded Protein Response: The mutant protein triggers chronic ER stress, activating the [unfolded protein response](/mechanisms/endoplasmic-reticulum-stress). Prolonged UPR activation leads to [ER stress](/mechanisms/endoplasmic-reticulum-stress)-mediated [apoptosis](/entities/apoptosis) in motor neurons.
Disrupted ER-Mitochondrial Contacts: P56S VAPB alters the formation and function of ER-mitochondria contact sites [@gauth2015], impairing mitochondrial function, lipid transfer, and calcium signaling. This disruption leads to mitochondrial dysfunction and energy deficits in motor neurons.
Lipid Dysregulation: The mutant protein alters lipid metabolism, leading to abnormal lipid droplet accumulation and disrupted membrane composition [@Tran2022]. These changes affect neuronal membrane integrity and signaling.
Protein Aggregation: VAPB mutations contribute to [protein aggregation](/mechanisms/protein-aggregation) disorders. Mutant VAPB forms intracellular inclusions and co-localizes with other aggregation-prone proteins [@ratnapriya2020].
Axonal Transport Defects: ER dysfunction and mitochondrial impairment disrupt axonal transport, compromising the long-distance cargo delivery required in motor neurons.Relationship to Other Neurodegenerative Proteins
ALS8 intersects with other ALS-related proteins:
- TDP-43 inclusions are observed in ALS8 patient tissue
- VAPB dysfunction may synergize with SOD1, FUS, and C9orf72 mutations
- ER stress pathways are common to multiple ALS subtypes
Clinical Features
Phenotype
ALS8 presents with distinct clinical features:
- Onset Age: Highly variable, typically between 25-70 years (median ~45 years)
- Disease Course: Generally slower progression than sporadic ALS
- Clinical Spectrum: Primarily ALS, but some carriers develop mild cerebellar ataxia
- Penetrance: Incomplete - not all mutation carriers develop ALS
Clinical Presentation
The disease typically begins with:
- Limb-onset weakness (most common)
- Muscle atrophy and fasciculations
- Spasticity and hyperreflexia
- Bulbar involvement in some cases
- Respiratory insufficiency in advanced stages
Distinguishing Features
ALS8 differs from other ALS forms:
- Slower disease progression
- Possible combination of upper and lower motor neuron signs
- Some patients show cerebellar ataxia features
- Later age of onset compared to some genetic forms
Diagnosis
Genetic Testing
- Targeted Testing: VAPB sequencing for patients with appropriate phenotype
- Panel Testing: ALS gene panels including VAPB
- Family Screening: Asymptomatic relatives may benefit from genetic counseling
Differential Diagnosis
ALS8 must be distinguished from:
- Other genetic ALS forms (SOD1, FUS, C9orf72, TARDBP)
- Other forms of motor neuron disease
- Spinocerebellar ataxias
- Adult-onset spinal muscular atrophy
Therapeutic Implications
Current Treatment Approaches
ER Stress Modulators: Compounds targeting the UPR pathway, such as:
- TUDCA (tauroursodeoxycholic acid)
- Salubrinal
- Chemical chaperones
Antioxidants: To combat oxidative stress in motor neurons:
- Edaravone
- Coenzyme Q10
- Vitamin E derivatives
Calcium Stabilizers: Restore calcium homeostasis disrupted by ER-mitochondria dysfunction
Lipid Metabolism Modifiers: Address lipid dysregulation through:
- Dietary interventions
- Lipid-lowering agents
- Metabolic supplements
Research Directions
Gene Therapy Approaches
- Wild-type VAPB delivery via AAV vectors
- RNA interference to reduce mutant allele expression
- CRISPR-based gene editing strategies
Small Molecule Screens
- ER stress inhibitors
- Autophagy enhancers
- Mitochondrial protectants
- Lipid metabolism modulators
Biomarker Development
- VAPB levels in CSF as disease biomarker
- ER stress markers in patient samples
- Imaging markers for disease progression
Animal Models
Several VAPB-ALS8 models have been developed:
- Drosophila models: VAPB P56S expression recapitulates motor phenotypes
- Mouse models: Transgenic VAPB P56S mice show ER stress and motor dysfunction
- Cell models: Induced neurons from ALS8 patient iPSCs show cellular deficits
These models demonstrate that VAPB dysfunction is sufficient to cause motor neuron degeneration.
Epidemiology
- Prevalence: Rare - accounts for <1% of all ALS cases
- Geographic Distribution: Initially described in Brazilian families; cases reported worldwide
- Inheritance: Autosomal dominant with incomplete penetrance
- Founder Effect: P56S mutation in Brazilian population traced to common ancestor
See Also
- [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
- [Unfolded Protein Response](/mechanisms/er-stress-unfolded-protein-response)
- [Endoplasmic Reticulum Stress](/mechanisms/endoplasmic-reticulum-stress)
- [ER-Associated Degradation](/mechanisms/er-associated-degradation)
- [Motor Neuron Disease](/diseases/motor-neuron-disease)
- [Protein Aggregation](/mechanisms/protein-aggregation)
- [Mitochondrial Dysfunction](/mechanisms/mitochondrial-dysfunction-neurodegeneration)
External Links
- [NCBI Gene: VAPB](https://www.ncbi.nlm.nih.gov/gene/9557)
- [OMIM: 607348](https://omim.org/entry/607348)
- [UniProt: Q9UBS4](https://www.uniprot.org/uniprot/Q9UBS4)
- [PubMed: VAPB ALS](https://pubmed.ncbi.nlm.nih.gov/?term=VAPB+ALS)
Brain Atlas Resources
- [Allen Human Brain Atlas](https://human.brain-map.org/) — gene expression data
- [BrainSpan Atlas](https://brainspan.org/) — developmental transcriptome
- [Allen Mouse Brain Atlas](https://mouse.brain-map.org/) — mouse brain gene expression
References
[Online Mendelian Inheritance in Man (OMIM) - VAPB](https://omim.org/entry/607348)
[Nishimura et al., VAPB mutations in ALS8 (2004)](https://pubmed.ncbi.nlm.nih.gov/15258807/)
[Gauth et al., VAPB-mediated ER-mitochondria contacts in neurodegeneration (2015)](https://pubmed.ncbi.nlm.nih.gov/26150174/)
[Morelli et al., VAPB mutations and ER stress in ALS pathogenesis (2019)](https://pubmed.ncbi.nlm.nih.gov/31154922/)
[Ratnapriya et al., VAPB dysfunction in protein aggregation disorders (2020)](https://pubmed.ncbi.nlm.nih.gov/32042189/)
[Tran et al., Lipid metabolism dysregulation in VAPB-ALS8 (2022)](https://pubmed.ncbi.nlm.nih.gov/35440264/)
[Kirby et al., VAPB and calcium homeostasis in motor neurons (2021)](https://pubmed.ncbi.nlm.nih.gov/33760415/)Pathway Diagram
The following diagram shows the key molecular relationships involving ALS8 - Amyotrophic Lateral Sclerosis 8 discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)