VPS13D Gene

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VPS13D Gene

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">VPS13D Gene</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>VPS13D</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>VPS13D</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=VPS13D" target="_blank">Search NCBI</a></td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/ms" style="color:#ef9a9a">Ms</a>, <a href="/wiki/parkinson" style="color:#ef9a9a">Parkinson</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">13 edges</a></td>
</tr>
</table>

Overview

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VPS13D Gene

Overview

Mermaid diagram (expand to render)

VPS13D (Vacuolar Protein Sorting 13 Homolog D) encodes a large peripheral membrane protein that functions in vesicle trafficking and [autophagy](/entities/autophagy). VPS13D is a member of the VPS13 family of proteins, which are involved in intracellular membrane transport and organelle dynamics [1]. Recently, VPS13D has been implicated in neurodegenerative diseases, particularly Alzheimer's disease and Parkinson's disease, due to its critical role in mitophagy and lysosomal function [2]. [@velayosbaeza2020]

Gene and Protein Structure

The VPS13D gene is located on chromosome 1p36.22 and is one of the largest genes in the human genome, spanning approximately 210 kb and consisting of 76 exons [3]. The encoded VPS13D protein is 4,377 amino acids in length, making it one of the largest proteins encoded by the human genome [4]. [@zhang2021]

VPS13D contains multiple functional domains: [@ucsc2023]

N-terminal chorein domain: Named after the chorein protein deficient in chorea-acanthocytosis
VPS13 core domain: Highly conserved region involved in membrane interactions
C-terminal domains: Multiple predicted domains for protein-protein interactions [5]

The protein localizes to the outer mitochondrial membrane and is involved in mitochondrial dynamics [6]. [@uniprot2023]

Role in Neurodegeneration

Alzheimer's Disease

VPS13D plays important roles in Alzheimer's disease (AD): [@lees2019]

Mitophagy regulation: VPS13D is essential for mitophagy, the selective autophagy of damaged mitochondria. Impaired mitophagy contributes to mitochondrial dysfunction in AD [7].
[Amyloid-beta](/proteins/amyloid-beta) metabolism: VPS13D affects [APP](/entities/app-protein) processing and Aβ production through its role in endosomal/lysosomal trafficking [8].
[Tau](/proteins/tau) pathology: Proper VPS13D function is required for lysosomal degradation of tau aggregates [9].
Neuronal survival: VPS13D deficiency leads to mitochondrial dysfunction and neuronal death [10].

Parkinson's Disease

In Parkinson's disease (PD), VPS13D is particularly important: [@anding2021]

PINK1/Parkin pathway: VPS13D acts downstream of PINK1 and Parkin in mitophagy, which is central to PD pathogenesis [11].
Mitochondrial quality control: VPS13D is crucial for maintaining mitochondrial health in dopaminergic [neurons](/entities/neurons) [12].
[α-Synuclein](/proteins/alpha-synuclein) clearance: VPS13D-mediated mitophagy affects the clearance of α-synuclein aggregates [13].
Dopaminergic neuron vulnerability: The high energy requirements of dopaminergic neurons make them particularly dependent on VPS13D function [14].

Other Neurodegenerative Disorders

Huntington's Disease: VPS13D dysfunction may contribute to mitochondrial abnormalities in HD [15]
Spinocerebellar Ataxias: VPS13D variants have been associated with autosomal recessive ataxias [16]
Amyotrophic Lateral Sclerosis: Mitophagy defects involving VPS13D may contribute to motor neuron degeneration [17]

Expression Patterns

VPS13D is widely expressed with high levels in: [@khandelwal2022]

Brain: Highest expression in the cerebral [cortex](/brain-regions/cortex), [hippocampus](/brain-regions/hippocampus), and cerebellum
Heart: High cardiac expression reflecting mitochondrial demand
Skeletal muscle: Muscle tissues with high mitochondrial content
Liver: Hepatic expression for metabolic function [18]

In the brain, VPS13D is expressed in: [@wang2021]

Cortical pyramidal neurons
Hippocampal neurons (CA1-CA3, dentate gyrus)
Cerebellar Purkinje cells
Substantia nigra dopaminergic neurons
[Astrocytes](/entities/astrocytes) and [microglia](/cell-types/microglia-neuroinflammation) [19]

Therapeutic Implications

VPS13D is an emerging therapeutic target: [@lee2022]

Mitophagy enhancement: Small molecules that enhance VPS13D-mediated mitophagy are being investigated [20]
Gene therapy: AAV-mediated VPS13D overexpression may protect neurons [21]
Protein stabilization: Compounds that stabilize VPS13D protein are of interest [22]

Interactions and Pathways

VPS13D interacts with multiple proteins and pathways: [@tang2021]

PINK1/Parkin pathway: Functions downstream of mitochondrial depolarization
Atg proteins: Part of the core autophagy machinery
Mitochondrial dynamics proteins: Interacts with fission and fusion proteins
Lysosomal proteins: Involved in late endosome/lysosome function [23]

Research Findings

Key research findings on VPS13D in neurodegeneration: [@lazarou2020]

VPS13D loss-of-function causes a rare neurodevelopmental disorder with ataxia and spasticity [24]

Knockdown of VPS13D leads to mitochondrial dysfunction and cell death in neuronal cultures [25]

VPS13D variants are associated with PD risk in genome-wide studies [26]

VPS13D is required for efficient clearance of damaged mitochondria by mitophagy [27]

Drosophila models of VPS13D deficiency show neurodegeneration [28]

Summary

VPS13D encodes a large peripheral membrane protein essential for mitochondrial quality control through mitophagy. Dysregulation of VPS13D contributes to the pathogenesis of Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders by impairing mitochondrial and lysosomal function. Understanding VPS13D's role in neuronal survival may reveal novel therapeutic targets. [@mcwilliams2021]

Additional evidence sources: [@sato2022] [@vincow2019] [@klein2021] [@gasser2020] [@bhide2022] [@gtex2023] [@allen2023] [@fivenson2021] [@esser2022] [@miller2021] [@kluge2021] [@baczewska2022] [@tang2021a] [@nalls2019] [@anding2021a] [@rujavanich2022]

VPS13D Gene

VPS13D Gene

Overview

VPS13D Gene

Overview

Gene and Protein Structure

Role in Neurodegeneration

Alzheimer's Disease

Parkinson's Disease

Other Neurodegenerative Disorders

Expression Patterns

Therapeutic Implications

Interactions and Pathways

Research Findings

Summary

See Also