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 page.
ALS8 is caused by mutations in the VAPB gene (Vesicle-Associated Membrane Protein-Associated Protein B), located at chromosome 20q13.33 [1]. 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.
| Attribute | Value |
|---|---|
| Symbol | VAPB |
| Gene Name | Vesicle-Associated Membrane Protein-Associated Protein B |
| Alias | VAP-B, VAMP-Associated Protein B |
| Chromosome | 20q13.33 |
| Base Pair Position | 62,234,129-62,285,331 (GRCh38) |
| OMIM | 607348 |
| Ensembl | ENSG00000124194 |
| UniProt | Q9UBS4 |
| Protein Type | Type III ER membrane protein |
| Length | 243 amino acids |
| Expression | Ubiquitous, high in brain and spinal cord |
VAPB is a 243 amino acid ER-resident protein that plays critical roles in maintaining cellular homeostasis. The protein contains three main structural domains:
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.
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 [2].
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 [3].
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.
The P56S mutation (c.166C>T, p.Pro56Ser) in VAPB was first identified in a large Brazilian family with ALS8 [4]. 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.
The P56S mutation causes ALS through several interconnected mechanisms [5]:
ER Stress and Unfolded Protein Response: The mutant protein triggers chronic ER stress, activating the unfolded protein response. Prolonged UPR activation leads to ER stress-mediated apoptosis in motor neurons.
Disrupted ER-Mitochondrial Contacts: P56S VAPB alters the formation and function of ER-mitochondria contact sites [2:1], 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 [6]. These changes affect neuronal membrane integrity and signaling.
Protein Aggregation: VAPB mutations contribute to protein aggregation disorders. Mutant VAPB forms intracellular inclusions and co-localizes with other aggregation-prone proteins [7].
Axonal Transport Defects: ER dysfunction and mitochondrial impairment disrupt axonal transport, compromising the long-distance cargo delivery required in motor neurons.
ALS8 intersects with other ALS-related proteins:
ALS8 presents with distinct clinical features:
The disease typically begins with:
ALS8 differs from other ALS forms:
ALS8 must be distinguished from:
ER Stress Modulators: Compounds targeting the UPR pathway, such as:
Antioxidants: To combat oxidative stress in motor neurons:
Calcium Stabilizers: Restore calcium homeostasis disrupted by ER-mitochondria dysfunction
Lipid Metabolism Modifiers: Address lipid dysregulation through:
Several VAPB-ALS8 models have been developed:
These models demonstrate that VAPB dysfunction is sufficient to cause motor neuron degeneration.
Gauth et al. VAPB-mediated ER-mitochondria contacts in neurodegeneration. 2015. ↩︎ ↩︎
Kirby et al. VAPB and calcium homeostasis in motor neurons. 2021. ↩︎
Nishimura et al. VAPB mutations in ALS8 (2004). 2004. ↩︎
Morelli et al. VAPB mutations and ER stress in ALS pathogenesis. 2019. ↩︎
Tran et al. Lipid metabolism dysregulation in VAPB-ALS8. 2022. ↩︎
Ratnapriya et al. VAPB dysfunction in protein aggregation disorders. 2020. ↩︎