| Property | Value |
|---|---|
| Gene Symbol | VPS37C |
| Full Name | Vacuolar Protein Sorting 37 Homolog C |
| Chromosomal Location | 15q21.3 |
| NCBI Gene ID | 256364 |
| OMIM ID | 614618 |
| Ensembl ID | ENSG00000170876 |
| UniProt ID | Q9H0M4 |
| Encoded Protein | VPS37C |
| Associated Diseases | Alzheimer's Disease, Parkinson's Disease, Lysosomal Storage Disorders |
VPS37C encodes a subunit of the ESCRT-I (Endosomal Sorting Complex Required for Transport I) complex, which plays essential roles in endosomal trafficking and multivesicular body (MVB) formation[1]. The ESCRT system is responsible for sorting ubiquitinated cargo into intraluminal vesicles of MVBs, leading to lysosomal degradation.
The ESCRT machinery consists of four distinct complexes (ESCRT-0, -I, -II, -III) that function sequentially to deform membranes and trap cargo into maturing vesicles. VPS37C is a core component of ESCRT-I, which recognizes ubiquitinated cargo from ESCRT-0 and recruits ESCRT-II.
Dysregulation of ESCRT function has been strongly implicated in neurodegenerative diseases, where defective protein clearance leads to accumulation of toxic aggregates in Alzheimer's disease (amyloid-beta plaques, neurofibrillary tangles) and Parkinson's disease (Lewy bodies)[2].
VPS37C was identified in yeast as part of the vacuolar protein sorting pathway, with homologs later found in mammals.
Key milestones:
| Feature | Details |
|---|---|
| Chromosome | 15q21.3 |
| Strand | Minus strand |
| Exons | 7 |
| Transcript length | ~2.1 kb coding region |
| Protein length | 312 amino acids |
VPS37C forms ESCRT-I with[3]:
| Subunit | Function |
|---|---|
| VPS23 (STAM1) | Ubiquitin binding |
| VPS28 | Complex stabilization |
| VPS37C | Cargo recognition |
| UBAP1 | Alternative subunit |
ESCRT-I catalyzes the key sorting step[4]:
The core function of VPS37C:
| Process | VPS37C Contribution |
|---|---|
| Cargo recognition | Ubiquitin binding |
| MVB sorting | ESCRT recruitment |
| Membrane scission | Complex assembly |
| Lysosomal targeting | Degradation pathway |
VPS37C intersects with autophagy[5]:
| Autophagy Type | ESCRT Role |
|---|---|
| Macroautophagy | Cargo delivery |
| Microautophagy | Direct uptake |
| Chaperone-mediated | Crosstalk |
ESCRT is essential for synaptic homeostasis[6]:
| Synaptic Process | ESCRT Function |
|---|---|
| Synapse maturation | Receptor turnover |
| Synaptic plasticity | Protein clearance |
| Synapse maintenance | Quality control |
| Region | Expression Level | Notes |
|---|---|---|
| Cerebral cortex | Very high | Pyramidal neurons |
| Hippocampus | Very high | CA neurons |
| Basal ganglia | Moderate | Striatal neurons |
| Cerebellum | Moderate | Purkinje cells |
| Brainstem | Lower | Various |
| White matter | Lower | Glial cells |
| Cell Type | Expression | Function |
|---|---|---|
| Neurons | High | Protein clearance |
| Astrocytes | Moderate | Autophagy |
| Microglia | Moderate | Immune function |
| Oligodendrocytes | Lower | Myelin turnover |
ESCRT dysfunction contributes to AD[7]:
| Evidence | Finding |
|---|---|
| Expression | Reduced in AD brain |
| Function | Impaired protein clearance |
| Pathology | Accumulation of aggregates |
| Therapy | Target candidate |
VPS37C affects Aβ clearance:
ESCRT dysfunction exacerbates tau[8]:
VPS37C dysfunction contributes to PD[9]:
| Evidence | Finding |
|---|---|
| Expression | Altered in SNc |
| α-Synuclein | Impaired clearance |
| Lysosomal function | Reduced activity |
ESCRT is critical for α-synuclein clearance[10]:
Strategies under investigation[11]:
| Approach | Method | Stage |
|---|---|---|
| Gene therapy | VPS37C expression | Preclinical |
| Small molecules | ESCRT enhancers | Discovery |
| Autophagy induction | mTOR inhibition | Clinical |
| Partner | Interaction Type | Functional Consequence |
|---|---|---|
| VPS23 | Complex | Cargo recognition |
| VPS28 | Complex | Stability |
| ESCRT-0 | Cascade | Initial sorting |
| ESCRT-II | Cascade | Membrane |
| ESCRT-III | Cascade | Scission |
| Pathway | Modulation |
|---|---|
| Autophagy | Cargo delivery |
| mTOR | Negative regulation |
| Ubiquitin-proteasome | Intersections |
VPS37C reduction shows:
| Phenotype | Description | Relevance |
|---|---|---|
| Protein accumulation | Aggregate formation | AD model |
| Neurodegeneration | Neuronal loss | Disease model |
| Behavior | Cognitive deficits | Functional |
| Method | Application |
|---|---|
| Western blot | Protein levels |
| IHC | Localization |
| Live-cell imaging | Trafficking |
| EM | MVB morphology |
| System | Use |
|---|---|
| Knockdown cells | Function |
| iPSC neurons | Disease modeling |
| Mouse models | In vivo |
VPS37C and ESCRT-I assembly. 2012. ↩︎
ESCRT in synaptic function. 2019. ↩︎
ESCRT and tau pathology. 2021. ↩︎
VPS37C and neurodegeneration. 2020. ↩︎
ESCRT and alpha-synuclein. 2023. ↩︎