VPS33A Gene

VPS33A Gene

Introduction

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">VPS33A Gene</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>VPS33A</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>VPS33A</td>
</tr>
<tr>
<td class="label">Type</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">NCBI</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/?term=VPS33A" target="_blank">Search NCBI</a></td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">12 edges</a></td>
</tr>
</table>

Vps33A Gene is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

VPS33A Gene

Introduction

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">VPS33A Gene</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>VPS33A</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>VPS33A</td>
</tr>
<tr>
<td class="label">Type</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">NCBI</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/?term=VPS33A" target="_blank">Search NCBI</a></td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">12 edges</a></td>
</tr>
</table>

Vps33A Gene is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

VPS33A (Vacuolar Protein Sorting 33 Homolog A) encodes a Sec1/Munc18-family membrane-fusion regulator that acts in the late endosome-lysosome system. In mammalian cells, VPS33A is a core component of the HOPS tethering complex, which coordinates membrane tethering and SNARE-dependent fusion during endolysosomal maturation and autophagosome clearance.[@balderhaar2013][@brcker2012] Because [neurons](/entities/neurons) depend on efficient long-range cargo turnover and lysosomal proteostasis, disruption of VPS33A-linked trafficking can amplify proteotoxic stress relevant to [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), and related proteinopathies.[@nixon2013][@menzies2015]

Gene And Protein Context

VPS33A is located on chromosome 12q24.31 and encodes a cytosolic SM-family protein that is recruited to membranes through its interactions with other HOPS subunits, including VPS11, VPS16, VPS18, VPS39, and VPS41.[@balderhaar2013][@brcker2012] Functionally, VPS33A acts as a scaffold that helps assemble fusion-competent SNARE complexes downstream of Rab7-positive late endosome positioning.[@balderhaar2013][@van2021]

Compared with the related paralog VPS33B, VPS33A is preferentially associated with canonical endolysosomal and autophagosome-lysosome fusion routes, while VPS33B participates more strongly in specialized trafficking programs in selected tissues.[@hunter2017] This distinction is useful when interpreting cell-type-specific phenotypes in the brain, where VPS33A-dependent flux is tightly coupled to synaptic and mitochondrial quality control.[@nixon2013][@menzies2015]

Molecular Function In HOPS-Mediated Fusion

1. Endosome-to-Lysosome Progression

Late endosomes carry cargo destined for degradation and mature through Rab conversion, acidification, and tethering events. HOPS bridges apposed membranes and positions SNARE proteins for lipid bilayer fusion; VPS33A is the catalytic SM-family unit that stabilizes SNARE assembly within this complex.[@balderhaar2013][@brcker2012]

2. Autophagosome-Lysosome Fusion

Macroautophagy requires completed autophagosomes to fuse with lysosomes before hydrolase-mediated cargo degradation can occur. VPS33A contributes at this terminal fusion checkpoint, making it mechanistically upstream of aggregate clearance pathways involving [alpha-synuclein](/proteins/alpha-synuclein), [tau](/proteins/tau), and damaged mitochondria.[@nixon2013][@lie2019]

3. Lysosomal Homeostasis And Signaling

When VPS33A-HOPS activity is reduced, cells accumulate cargo-positive vesicles, show delayed autophagic flux, and exhibit secondary stress responses (including inflammatory and mitochondrial stress programs).[@nixon2013][@lie2019] In neurons and glia, these failures can propagate network-level vulnerability by increasing extracellular proteotoxic burden and impairing metabolic resilience.[@menzies2015][@moors2017]

Relevance To Neurodegeneration

Proteostasis Pressure In Vulnerable Neurons

Selective neuronal populations with high axonal arborization and synaptic turnover have unusually high reliance on endolysosomal throughput. In these contexts, partial VPS33A dysfunction can shift the system from compensable delay to progressive cargo backlog, promoting convergence with [autophagy dysfunction](/mechanisms/autophagy-dysfunction) and [lysosomal dysfunction](/mechanisms/lysosomal-dysfunction) pathways.[@nixon2013][@menzies2015]

Parkinsonian Mechanistic Links

In PD-relevant models, impairment of lysosomal trafficking increases persistence of aggregation-prone proteins and reduces mitophagy efficiency. These effects are mechanistically aligned with broader pathways involving [GBA1](/genes/gba1), [LRRK2](/genes/lrrk2), and [SNCA](/genes/snca), where vesicle trafficking and lysosome competence strongly modulate disease progression.[@menzies2015][@moors2017]

Alzheimer's-Disease Mechanistic Links

AD biology also intersects VPS33A-regulated routes through autophagic vacuole handling, endosomal stress, and clearance burden created by amyloid and [tau](/proteins/tau) pathology. In this framing, VPS33A is not only a trafficking gene but part of a systems-level resilience module that buffers chronic proteotoxic load.[@nixon2013][@lie2019]

Experimental And Translational Considerations

Biomarker-Relevant Readouts

VPS33A pathway status is often inferred indirectly using:

• late endosome/lysosome morphology,
• LC3-II and cargo receptor turnover dynamics,
• autolysosome formation assays,
• and accumulation of undegraded neuronal cargo.[@balderhaar2013][@nixon2013]

Intervention Strategies

Current translational strategies generally do not target VPS33A directly, but instead attempt to restore pathway throughput by:

• increasing lysosomal biogenesis,
• improving autophagosome maturation,
• lowering aggregate seeding pressure,
• or combining trafficking support with anti-inflammatory therapy.[@nixon2013][@menzies2015][@moors2017]

Background

The study of Vps33A Gene 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.

Cross-References

• [VPS16 Gene](/genes/vps16)
• [VPS8 Gene](/genes/vps8)
• [VPS41 Gene](/genes/vps41)
• [Autophagy Dysfunction](/mechanisms/autophagy-dysfunction)
• [Lysosomal Dysfunction](/mechanisms/lysosomal-dysfunction)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Alzheimer's Disease](/diseases/alzheimers-disease)

See Also

• [VPS Proteins](/proteins/vps-proteins) — Vacuolar protein sorting family
• [Endolysosomal System](/mechanisms/endolysosomal-system) — Cellular trafficking pathway
• [Autophagy](/mechanisms/autophagy-lysosomal-pathway) — Degradation pathway
• [Lysosomal Storage Disorders](/diseases/lysosomal-storage-disorders) — Diseases with VPS dysfunction

External Links

• [NCBI Gene: VPS33A](https://www.ncbi.nlm.nih.gov/gene/65078)
• [UniProt: VPS33A (Q9NZJ8)](https://www.uniprot.org/uniprot/Q9NZJ8)

Brain Atlas Resources

• [Allen Human Brain Atlas - VPS33A](https://human.brain-map.org/microarray/search/show?search_term=VPS33A)
• [Allen Brain Map Portal](https://portal.brain-map.org/)
• [BrainSpan Atlas of the Developing Human Brain](https://brainspan.org/)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving VPS33A Gene discovered through SciDEX knowledge graph analysis:

Expression Profile

Sources: [GTEx Portal v10](https://gtexportal.org/home/gene/vps33a) | [Allen Brain Atlas](https://www.brain-map.org/)

GTEx Tissue Expression (median TPM)

| Rank | Tissue | Median TPM |
|------|--------|------------|
| 1 | Testis | 25.27 |
| 2 | Pituitary | 17.03 |
| 3 | Cells EBV-transformed lymphocytes | 15.22 |
| 4 | Brain Cerebellar Hemisphere | 14.84 |
| 5 | Cells Cultured fibroblasts | 14.07 |
| 6 | Brain Cerebellum | 13.66 |
| 7 | Uterus | 12.69 |
| 8 | Spleen | 12.45 |
| 9 | Cervix Endocervix | 11.57 |
| 10 | Fallopian Tube | 11.56 |
| 11 | Bladder | 11.54 |
| 12 | Artery Tibial | 11.25 |
| 13 | Nerve Tibial | 10.89 |
| 14 | Colon Sigmoid | 10.54 |
| 15 | Adrenal Gland | 10.53 |

Brain-Region Expression:

| Region | Median TPM |
|--------|------------|
| Brain Cerebellar Hemisphere | 14.84 |
| Brain Cerebellum | 13.66 |