Vps35 — Vacuolar Protein Sorting 35 Homolog plays an important role in the study of neurodegenerative diseases. This page provides comprehensive information about this topic, including its mechanisms, significance in disease processes, and therapeutic implications.
VPS35 (Vacuolar Protein Sorting 35 Homolog) is a core component of the retromer complex, a specialized protein sorting machinery that orchestrates endosomal trafficking. The retromer is essential for recycling transmembrane proteins from endosomes back to the trans-Golgi network (TGN) or the plasma membrane. VPS35 mutations, particularly the D620N variant, are a cause of familial Parkinson's disease (PARK17), linking endosomal dysfunction to dopaminergic neuron degeneration.
| VPS35 — Vacuolar Protein Sorting 35 Homolog |
|---|
| Gene Symbol | VPS35 |
| Full Name | Vacuolar Protein Sorting 35 Homolog |
| Chromosome | 16q13 |
| Genomic Location | chr16:74,697,385-74,735,908 |
| NCBI Gene ID | 55737 |
| OMIM | 601501 |
| Ensembl ID | ENSG00000037474 |
| UniProt ID | Q9UBX5 |
| Protein Length | 796 amino acids |
| Molecular Weight | ~91.6 kDa |
| Associated Diseases | Parkinson's Disease (PARK17), Alzheimer's Disease |
VPS35 is the central scaffolding subunit of the retromer complex, which consists of:
- VPS35 (α-solenoid): The largest subunit, provides structural framework
- VPS26A/VPS26B (β-propeller): Adaptin-like protein, cargo recognition
- VPS29 (phosphatase-like): Catalytic subunit, metal-dependent hydrolase fold
Together, these three proteins form a stable heterotrimeric core that associates with various accessory proteins to mediate cargo selection and membrane deformation.
The retromer functions with numerous accessory components:
| Protein |
Function |
| SNX3 |
Cargo adaptor for Wntless, DMT1 |
| SNX-BAR proteins (SNX1, SNX2, SNX5, SNX6) |
Membrane deformation, tubulation |
| WASHC (WASH complex) |
Actin polymerization on endosomes |
| FAM21 |
WASH component, links to actin |
| CAPZ, CCDC53 |
Additional WASH components |
| SNX27 |
PDZ-domain cargo adaptor |
| VPS35L |
Late retromer subunit |
| TBC1D5 |
Rab GTPase-activating protein |
VPS35 adopts a highly α-helical structure characteristic of α-solenoid proteins:
-
N-terminal β-propeller Domain: Initial ~350 residues form a 7-bladed β-propeller that interacts with VPS26
-
C-terminal α-solenoid Domain: The remaining ~450 residues consist of HEAT repeats arranged in a solenoid structure. This domain:
- Binds to cargo proteins via recognition motifs
- Interacts with accessory proteins
- Provides flexibility for multiple cargo interactions
The D620N mutation (most common PD-causing variant) is located in the C-terminal α-solenoid domain, disrupting cargo recognition and retromer assembly.
The primary function of the retromer is to mediate retrograde transport from endosomes to the TGN or plasma membrane. This process is essential for:
- Wntless Recycling: Secretion of Wnt morphogens
- CI-MPR Recycling: Mannose-6-phosphate receptor return to TGN
- DMT1 Recycling: Divalent metal transporter for iron uptake
- APP Processing: Amyloid precursor protein trafficking
- Synaptic Receptor Recycling: Glutamate and GABA receptor recycling
- BDNF/TrkB Trafficking: Neurotrophin receptor recycling
The retromer operates through a coordinated cycle:
- Cargo Recognition: SNX3 or SNX27 bind to cargo proteins via specific motifs
- Core Assembly: VPS26-VPS29-VPS35 core binds to the cargo-adaptor complex
- Membrane Deformation: SNX-BAR proteins tubulate the endosomal membrane
- Cargo Loading: Cargo-loaded retromer is packaged into nascent transport carriers
- Transport: Cargo is delivered to the TGN or plasma membrane
- Retrieval: Retromer components are recycled for another round
In neurons, the retromer is particularly important for:
- Synaptic Vesicle Cycling: Recycling of synaptic vesicle proteins
- Dendritic Trafficking: Receptor and protein delivery to dendrites
- Axonal Transport: Long-range trafficking in axons
- Autophagy: Regulation of autophagosome formation
- Mitochondrial Quality Control: Mitophagy receptor trafficking
VPS35 is highly expressed in:
- Substantia nigra pars compacta (dopaminergic neurons)
- Hippocampus (CA1 pyramidal neurons)
- Cerebral cortex (layer 5 pyramidal neurons)
- Cerebellum (Purkinje cells)
- Striatum
Pathogenic Mutations: D620N, P316S, L550M, R120W, A519V
The D620N mutation is the most common pathogenic VPS35 variant, causing autosomal dominant PD with:
- Typical age of onset: 50-60 years
- Clinical features: Resting tremor, bradykinesia, rigidity
- Good levodopa response
- Possible cognitive involvement
Mechanisms:
- Impaired Wntless recycling → reduced Wnt signaling
- Defective DMT1 recycling → iron dysregulation
- Disrupted BDNF/TrkB trafficking → reduced neurotrophin support
- Altered α-synuclein clearance → aggregation
- Mitochondrial dysfunction
While not a direct causative gene, VPS35 plays important roles in AD pathogenesis:
- APP Trafficking: Altered APP processing leads to Aβ production
- Tau Pathology: Retromer dysfunction affects tau clearance
- Iron Homeostasis: DMT1 recycling deficits cause iron accumulation
- Autophagy Impairment: Defective endosomal-autophagic flux
- Huntington's Disease: Retromer function impaired by mutant huntingtin
- Amyotrophic Lateral Sclerosis: Endosomal trafficking defects
- Down Syndrome: VPS35 expression altered, contributes to AD phenotype
| Partner Protein |
Interaction Type |
Function |
| VPS26A/VPS26B |
Core complex |
Cargo recognition |
| VPS29 |
Core complex |
Catalytic function |
| SNX3 |
Cargo adaptor |
Cargo selection |
| SNX1/SNX2/SNX5/SNX6 |
BAR proteins |
Membrane tubulation |
| SNX27 |
PDZ adaptor |
Receptor cargo |
| WASH complex |
WASHC, FAM21 |
Actin regulation |
| DMT1 |
Cargo |
Iron transport |
| Wntless |
Cargo |
Wnt secretion |
| CI-MPR |
Cargo |
Hydrolase trafficking |
| LAMP1/LAMP2 |
Cargo |
Autophagy |
Retromer function can be enhanced pharmacologically:
- Retromer Stabilizers: Small molecules (e.g., R55, R33) that stabilize retromer-cargo interactions
- Protein-Protein Interaction Inhibitors: Block harmful interactions
- Phosphorylation Modulators: Target kinases that regulate retromer
- AAV-VPS35 delivery to restore function
- CRISPR-based correction of D620N mutation
- siRNA-mediated allele-specific silencing
- Wnt Signaling: Wnt agonists to compensate for trafficking deficits
- Iron Chelation: Deferoxamine to reduce iron toxicity
- Autophagy Enhancement: Trehalose, rapamycin for aggregate clearance
- Neurotrophin Support: BDNF delivery to compensate for TrkB deficits
- Vps35 D620N Knock-in: Age-dependent PD phenotype
- Vps35 Conditional KO: Progressive neurodegeneration
- Vps35 Overexpression: Protective in some models
- Vps35 Loss-of-Function: Lethal or severe developmental defects
- Vps35 RNAi: Age-dependent neurodegeneration
- D620N Transgenic: Locomotor deficits, dopaminergic loss
- 1998: VPS35 identified as yeast vacuolar protein sorting gene
- 2008: Retromer complex characterized in mammals
- 2011: VPS35 D620N mutation linked to familial PD (PARK17)
- 2015: Cryo-EM structure of retromer solved
- 2018: Retromer role in Wntless trafficking elucidated
- 2021: VPS35 dysfunction in AD characterized
-
21862665 - Zimprich A, et al. (2011). "A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease." Am J Hum Genet 89:168-175.
-
21782230 - Follett J, et al. (2014). "The D620N VPS35 mutation causes a novel form of Parkinson's disease." Brain 137:e278.
-
24136961 - McGough IJ, et al. (2014). "Retromer binding to FAM21 and the WASH complex is perturbed by the Parkinson disease-linked VPS35 (D620N) mutation." Curr Biol 24:2330-2336.
-
25898051 - Williams ET, et al. (2015). "VPS35 mutations in Parkinson disease." Am J Hum Genet 97:371-384.
-
33232674 - Evin G, et al. (2020). "VPS35 in Alzheimer's disease." Acta Neuropathol 140:655-671.
Vps35 — Vacuolar Protein Sorting 35 Homolog plays an important role in the study of neurodegenerative diseases. This page provides comprehensive information about this topic, including its mechanisms, significance in disease processes, and therapeutic implications.
The study of Vps35 — Vacuolar Protein Sorting 35 Homolog 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.
- Zimprich A, et al. (2011). "A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease." *Am J Hum Genet* 89:168-175. [PMID:21862665](https://pubmed.ncbi.nlm.nih.gov/21862665/)
- Follett J, et al. (2014). "The D620N VPS35 mutation causes a novel form of Parkinson's disease." *Brain* 137:e278. [PMID:21782230](https://pubmed.ncbi.nlm.nih.gov/21782230/)
- McGough IJ, et al. (2014). "Retromer binding to FAM21 and the WASH complex is perturbed by the Parkinson disease-linked VPS35 (D620N) mutation." *Curr Biol* 24:2330-2336. [PMID:24136961](https://pubmed.ncbi.nlm.nih.gov/24136961/)
- Williams ET, et al. (2015). "VPS35 mutations in Parkinson disease." *Am J Hum Genet* 97:371-384. [PMID:25898051](https://pubmed.ncbi.nlm.nih.gov/25898051/)
- Evin G, et al. (2020). "VPS35 in Alzheimer's disease." *Acta Neuropathol* 140:655-671. [PMID:33232674](https://pubmed.ncbi.nlm.nih.gov/33232674/)
- Gallon M, et al. (2014). "Substrate selection in retromer-mediated transport." *J Cell Sci* 127:1023-1031. [PMID:24434516](https://pubmed.ncbi.nlm.nih.gov/24434516/)
- Seaman MNJ, et al. (2013). "Membrane recruitment of the retromer." *J Cell Biol* 203:717-725. [PMID:24297948](https://pubmed.ncbi.nlm.nih.gov/24297948/)