VPS13C Protein

VPS13C Protein

Introduction

VPS13C (Vacuolar Protein Sorting 13 Homolog C) is a massive lipid transfer protein (~395 kDa, 3,589 amino acids) that serves as a critical bridge between organelles at membrane contact sites, shuttling lipids between the endoplasmic reticulum (ER), mitochondria, and lysosomes[@kumar2018]. First implicated in Parkinson's disease (PD) in 2016 through genetic studies identifying loss-of-function mutations causing autosomal recessive early-onset PD (PARK23), VPS13C has emerged as a central player in mitochondrial quality control, lipid homeostasis, and dopaminergic neuron survival[@lesage2016].

The discovery of VPS13C's role in neurodegeneration highlighted the importance of membrane contact site biology and lipid transfer in neuronal health. Unlike many PD-associated proteins involved in mitochondrial dynamics or autophagy individually, VPS13C integrates multiple cellular functions—lipid transport, ER-mitochondria communication, and mitophagy—making it a unique therapeutic target. This comprehensive page covers VPS13C's structure, normal physiological functions, disease mechanisms, and therapeutic implications.

VPS13C Protein

Introduction

VPS13C (Vacuolar Protein Sorting 13 Homolog C) is a massive lipid transfer protein (~395 kDa, 3,589 amino acids) that serves as a critical bridge between organelles at membrane contact sites, shuttling lipids between the endoplasmic reticulum (ER), mitochondria, and lysosomes[@kumar2018]. First implicated in Parkinson's disease (PD) in 2016 through genetic studies identifying loss-of-function mutations causing autosomal recessive early-onset PD (PARK23), VPS13C has emerged as a central player in mitochondrial quality control, lipid homeostasis, and dopaminergic neuron survival[@lesage2016].

The discovery of VPS13C's role in neurodegeneration highlighted the importance of membrane contact site biology and lipid transfer in neuronal health. Unlike many PD-associated proteins involved in mitochondrial dynamics or autophagy individually, VPS13C integrates multiple cellular functions—lipid transport, ER-mitochondria communication, and mitophagy—making it a unique therapeutic target. This comprehensive page covers VPS13C's structure, normal physiological functions, disease mechanisms, and therapeutic implications.

<div class="infobox infobox-protein">
<table>
<tr><th colspan="2"><strong>VPS13C</strong></th></tr>
<tr><td><strong>Full Name</strong></td><td>Vacuolar Protein Sorting 13 Homolog C</td></tr>
<tr><td><strong>Gene</strong></td><td>[VPS13C](/genes/vps13c)</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[Q96KM5](https://www.uniprot.org/uniprot/Q96KM5)</td></tr>
<tr><td><strong>Protein Size</strong></td><td>3,589 amino acids (~395 kDa)</td></tr>
<tr><td><strong>Protein Family</strong></td><td>VPS13 family</td></tr>
<tr><td><strong>Chromosomal Location</strong></td><td>15q22.2</td></tr>
<tr><td><strong>Subcellular Location</strong></td><td>ER-mitochondria contacts, Endolysosomes</td></tr>
<tr><td><strong>Associated Disease</strong></td><td>Parkinson's Disease (PARK23)</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/ms" style="color:#ef9a9a">Ms</a>, <a href="/wiki/parkinson's-disease" style="color:#ef9a9a">Parkinson's disease</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">13 edges</a></td>
</tr>
</table>
</div>

Overview

VPS13C is a member of the VPS13 family of lipid transfer proteins, which in humans includes four paralogs: VPS13A, VPS13B, VPS13C, and VPS13D. Each family member has distinct subcellular localization and biological functions, but all share a conserved domain architecture enabling lipid transport between organelles[@lees2017]. VPS13C localizes primarily to membrane contact sites between the ER and mitochondria, as well as ER-lysosome contacts, positioning it ideally to coordinate lipid flow and autophagy initiation.

The protein's functions can be summarized as follows:

Loss of VPS13C function leads to early-onset Parkinson's disease characterized by progressive dopaminergic neuron degeneration, typically beginning in the third or fourth decade of life[@van_der_merwe2017]. The disease mechanism involves accumulation of damaged mitochondria, impaired lipid homeostasis, and eventual α-synuclein pathology in surviving neurons[@correia2023].

Protein Structure

Domain Architecture

VPS13C contains several conserved domains that enable its diverse cellular functions[@dziurdzik2020]:

| Domain | Position | Function |
|--------|----------|----------|
| N-terminal chorein domain | 1-400 | Lipid binding pocket, forms hydrophobic groove |
| VPS13 core | 400-2500 | Structural scaffold, rod-like conformation |
| ATG2-like domain | 1800-2400 | Lipid transfer activity, membrane interaction |
| DUF1162 | 2500-3000 | Membrane targeting, phosphoinositide binding |
| C-terminal domain | 3000-3589 | Subcellular localization, protein interactions |

Structural Features

The VPS13C protein has unique structural characteristics that enable its lipid transfer function[@lees2017]:

• Chorein/N-terminal domain: Forms a hydrophobic groove that accommodates lipid molecules. The groove is lined with aromatic and hydrophobic residues that interact with the lipid tail while exposing the polar head group for recognition.
• Rod-like structure: The central VPS13 core adopts an extended rod-like conformation that can span distances of 10-20 nm between organelle membranes. This allows VPS13C to bridge membranes at contact sites without requiring direct membrane fusion.
• Membrane binding sites: Both N- and C-termini contain polybasic regions and hydrophobic motifs that bind to specific organelle membranes. The N-terminus preferentially binds ER membranes, while the C-terminus targets mitochondria and lysosomes.
• Phosphoinositide binding: The DUF1162 domain recognizes specific phosphoinositides (particularly PI4P and PI(4,5)P2) at contact sites, ensuring proper localization to ER-mitochondria and ER-lysosome contact sites.
• Flexible hinge regions: The protein contains flexible linker regions between domains that allow conformational changes during the lipid transfer cycle.

Comparison to VPS13 Family

VPS13C is one of four human VPS13 proteins, each with distinct cellular functions[@anding2017]:

| Protein | Localization | Primary Function | Disease Association |
|---------|--------------|------------------|---------------------|
| VPS13A | ER-lipid droplets | Lipid storage, trafficking | Chorea-acanthocytosis |
| VPS13B | ER-Golgi | Glycosylation, trafficking | Cohen syndrome |
| VPS13C | ER-mitochondria/lysosomes | Mitophagy, lipid transfer | Parkinson's disease (PARK23) |
| VPS13D | Mitochondria | Mitochondrial dynamics | Ataxia, spastic paraplegia |

The functional specialization of VPS13 family members reflects their distinct subcellular localizations and protein interaction networks. VPS13C's unique positioning at ER-mitochondria and ER-lysosome contact sites directly underlies its specific roles in mitophagy and endolysosomal function.

Normal Function

Lipid Transfer Mechanism

VPS13C transfers lipids between organelles at membrane contact sites through a coordinated mechanism[@kumar2018]:

The transfer mechanism proceeds as follows:

Organelle Contacts

VPS13C localizes to multiple membrane contact sites where organelles come into close proximity (within 10-30 nm)[@zhang2024]:

• ER-mitochondria contact sites (MAMs): VPS13C is highly enriched at mitochondria-associated membranes (MAMs) where the ER and mitochondria are apposed. These contacts are essential for calcium signaling, lipid transfer, and mitochondrial dynamics.
• ER-lysosome contact sites: VPS13C also localizes to contacts between the ER and late endosomes/lysosomes. These sites are important for lysosomal membrane maintenance and function.
• ER-lipid droplet contacts: A minor population of VPS13C associates with lipid droplets, though this is less prominent than for VPS13A.

Mitophagy Role

VPS13C is essential for mitochondrial quality control through mitophagy[@schorsch2020]:

Without VPS13C, the membrane supply for autophagosome formation is insufficient, resulting in impaired mitophagy and accumulation of damaged mitochondria[@park2020].

Lipidomic Functions

Beyond mitophagy, VPS13C contributes to cellular lipid homeostasis[@mueller2023]:

• Phospholipid composition: VPS13C helps maintain mitochondrial phospholipid composition, particularly cardiolipin and phosphatidylethanolamine, which are essential for mitochondrial function.
• Cholesterol trafficking: Some evidence suggests VPS13C participates in cholesterol transport between organelles.
• Lipid signaling: By modulating membrane lipid composition, VPS13C influences lipid signaling pathways including mTOR and AMPK signaling.

Role in Neurodegeneration

Parkinson's Disease

Loss of VPS13C function causes early-onset autosomal recessive Parkinson's disease through multiple interconnected mechanisms[@dhungel2019]:

Disease Characteristics

• Age of onset: Typically 20-40 years (early-onset PD)
• Disease progression: Progressive decline similar to idiopathic PD
• Clinical features: Tremor, bradykinesia, rigidity, often with psychiatric comorbidities
• Response to treatment: Levodopa responsive, but may develop motor complications

Pathogenic Mechanisms

Mitochondrial dysfunction: VPS13C deficiency leads to:

• Accumulation of dysfunctional mitochondria with reduced membrane potential
• Decreased ATP production, particularly problematic in energy-demanding dopaminergic neurons
• Increased production of reactive oxygen species (ROS)
• Impaired mitochondrial calcium handling
• Reduced mitophagy flux, creating a vicious cycle of damage accumulation["@park2020"]

• Lysosomal activity is reduced in VPS13C-deficient cells
• Accumulated alpha-synuclein may form toxic oligomers and fibrils
• alpha-Synuclein aggregation may further impair lysosomal function
• This creates a feed-forward cycle of toxicity["@correa2023"]

• High baseline energy requirements from dopamine synthesis and maintenance
• Dopamine metabolism generates oxidative stress via auto-oxidation and monoamine oxidase
• Mitochondrial dysfunction is particularly detrimental to these neurons
• The combination of energy deficit and oxidative stress overwhelms cellular protective mechanisms

Protein Aggregation

VPS13C deficiency may promote broader protein aggregation pathology:

• Impaired lysosomal degradation: Reduced lysosomal function affects clearance of various misfolded proteins
• Tau pathology: Some VPS13C-PD patients show tau pathology in addition to α-synuclein
• TDP-43: Evidence of TDP-43 pathology in some cases
• Aggregate seeding: Accumulated aggregates may seed further pathology

Cellular Phenotypes

VPS13C-deficient cells and neurons show characteristic abnormalities[@imai2021]:

Mitochondrial Abnormalities

• Fragmented mitochondria: Abnormal morphology with reduced length
• Reduced membrane potential: Impaired oxidative phosphorylation
• Accumulated PINK1: Persistent PINK1 on mitochondria indicates defective mitophagy
• Defective mitophagy: Autophagosomes fail to properly engulf mitochondria
• Increased ROS production: Oxidative stress from dysfunctional mitochondria

Lysosomal Defects

• Enlarged lysosomes: Impaired trafficking leads to enlarged, vacuolated lysosomes
• Reduced enzyme activity: Suboptimal lysosomal enzyme function or delivery
• Accumulated substrates: Storage-like phenotype with undigested material
• Membrane instability: Increased permeability and leakage

ER Stress

• Unfolded protein response: ER stress markers elevated
• Calcium dysregulation: Impaired ER-mitochondria calcium signaling
• Lipid droplet accumulation: Some cell models show lipid droplet accumulation

Disease-Causing Mutations

Pathogenic Variants

Several VPS13C mutations cause autosomal recessive PD[@van_der_merwe2017]:

| Mutation | Effect on Protein | Frequency |
|----------|-------------------|-----------|
| p.Arg1538* | Nonsense, truncation | Common |
| c.2382+1G>A | Aberrant splicing | European families |
| p.Gln2389*fs | Frameshift, premature stop | Various |
| p.Tyr1519Cys | Missense, loss of function | Multiple |
| Large deletions | Complete gene deletion | Rare |
| c.7528C>T | Nonsense mutation | Various |

Genotype-Phenotype Correlations

• Truncating mutations: Associated with earlier onset and more severe phenotype
• Missense mutations: Variable severity, may retain partial function
• Homozygous vs compound heterozygous: Both cause disease, severity may vary

Functional Consequences

Mutations cause disease through several mechanisms[@fecto2019]:

• Loss of lipid transfer: Impaired lipid shuttling between organelles
• Mislocalization: Protein cannot properly reach membrane contact sites
• Protein instability: Truncated proteins rapidly degraded
• Dominant-negative effects: Some mutants may interfere with wild-type function
• Impaired mitophagy: Failure to provide membrane for autophagosome formation

Therapeutic Targeting

Current Strategies

No VPS13C-specific therapies exist, but several approaches are being explored[@bandres2022]:

| Approach | Strategy | Challenge |
|----------|----------|-----------|
| Gene therapy | AAV-VPS13C delivery | Large gene size (~11 kb coding sequence) |
| Readthrough drugs | For nonsense mutations | Low efficiency, off-target effects |
| Mitophagy enhancers | Bypass VPS13C function | Non-specific, may have side effects |
| Lipid supplementation | Provide missing lipids | Delivery to correct organelles |
| mTOR inhibitors | Enhance autophagy | Broad effects, optimal dosing |

Drug Development Considerations

Several factors complicate VPS13C-targeted therapy:

• Large protein size: At 395 kDa, VPS13C cannot be delivered by traditional small molecules; gene therapy required
• Scaffold function: Proper subcellular localization is essential, not just protein presence
• Redundancy: Other VPS13 proteins cannot fully compensate for VPS13C loss
• Blood-brain barrier: CNS delivery required for neuroprotection
• Timing: Treatment likely needs to begin before significant neuron loss

Gene Therapy Approaches

• AAV vectors: Engineered AAVs can cross the BBB and deliver the VPS13C gene
• Promoter selection: Neuron-specific promoters to avoid off-target effects
• Dose optimization: Balancing efficacy with potential toxicity
• Readthrough compounds: Ataluren and similar drugs for nonsense mutations

Small Molecule Strategies

• Autophagy inducers: Trehalose, carbamazepine, rapamycin to enhance mitophagy
• mTOR-independent activators: Examples targeting TFEB or other pathways
• Mitochondrial protectants: CoQ10, MitoQ, other antioxidants
• Lipid metabolism modulators: Compounds affecting phospholipid metabolism

Biomarkers

Diagnostic Biomarkers

| Biomarker | Sample | Significance |
|-----------|--------|--------------|
| VPS13C protein levels | CSF, blood | Reduced in mutation carriers |
| PINK1 accumulation | Blood cells, neurons | Impaired mitophagy indicator |
| Mitochondrial DNA copy number | Blood, CSF | Compensation for dysfunction |
| Phospholipid profiles | Blood, CSF | Altered lipid homeostasis |

Disease Progression Markers

• Neuroimaging: DaT SPECT shows dopaminergic neuron loss
• Motor assessments: Unified Parkinson's Disease Rating Scale (UPDRS)
• Non-motor symptoms: Olfactory testing, sleep studies, neuropsychiatric evaluation

Therapeutic Response Markers

• Mitophagy markers: LC3-II/LC3-I ratio, p62 turnover
• Mitochondrial function: ATP levels, ROS production
• Lysosomal function: Cathepsin activity, substrate accumulation

Research Directions

Current Knowledge Gaps

• Structure: High-resolution structure of full-length VPS13C not yet determined
• Mechanism: Precise molecular mechanism of lipid transfer not fully characterized
• Regulation: How VPS13C activity is regulated in neurons
• Compensation: Whether other proteins can partially compensate
• Therapeutic window: Optimal timing for intervention

Ongoing Research

• iPSC models: Patient-derived neurons for disease modeling
• Animal models: Knockout and knock-in mouse models
• Structural studies: Cryo-EM analysis of VPS13C
• Compound screening: Small molecule libraries for autophagy enhancement

Key Publications

See Also

• [VPS13C Gene](/genes/vps13c)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Mitochondrial Dysfunction Pathway](/mechanisms/mitochondrial-dysfunction-pathway)
• [Autophagy-Lysosomal Pathway](/mechanisms/autophagy-lysosomal-pathway)
• [PINK1 Protein](/proteins/pink1-protein)
• [Parkin Protein](/proteins/parkin-protein)
• [Alpha-Synuclein Aggregation](/mechanisms/alpha-synuclein-aggregation-pathway)
• [GBA1 Gene](/proteins/gba1-protein)
• [ER-Mitochondria Contact Sites](/mechanisms/mitochondria-associated-membranes)
• [Lipid Transfer Proteins](/proteins/vps13-family)

External Links

• [UniProt: Q96KM5](https://www.uniprot.org/uniprot/Q96KM5)
• [NCBI Gene: VPS13C](https://www.ncbi.nlm.nih.gov/gene/55132)
• [OMIM: 616979](https://www.omim.org/entry/616979)
• [PDGene: VPS13C](https://www.pdgene.org/gene.details?acc=5116)
• [PubMed](https://pubmed.ncbi.nlm.nih.gov/?term=VPS13C+Parkinson)

References