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VPS35 in Dopamine Neurons Is Required for Endosome-to-Golgi Retrieval of Lamp2a, a Receptor of Chaperone-Mediated Autophagy That Is Critical for -Synuclein Degradation and Prevention of Pathogenesis of Parkinson's Disease
Open accessAbstract
Vacuolar protein sorting-35 (VPS35) is essential for endosome-to-Golgi retrieval of membrane proteins. Mutations in the VPS35 gene have been identified in patients with autosomal dominant PD. However, it remains poorly understood if and how VPS35 deficiency or mutation contributes to PD pathogenesis. Here we provide evidence that links VPS35 deficiency to PD-like neuropathology. VPS35 was expressed in mouse dopamine (DA) neurons in substantia nigra pars compacta (SNpc) and STR (striatum)--regions that are PD vulnerable. VPS35-deficient mice exhibited PD-relevant deficits including accumulation of α-synuclein in SNpc-DA neurons, loss of DA transmitter and DA neurons in SNpc and STR, and impairment of locomotor behavior. Further mechanical studies showed that VPS35-deficient DA neurons or DA neurons expressing PD-linked VPS35 mutant (D620N) had impaired endosome-to-Golgi retrieval of lysosome-associated membrane glycoprotein 2a (Lamp2a) and accelerated Lamp2a degradation. Expression of Lamp2a in VPS35-deficient DA neurons reduced α-synuclein, supporting the view for Lamp2a as a receptor of chaperone-mediated autophagy to be critical for α-synuclein degradation. These results suggest that VPS35 deficiency or mutation promotes PD pathogenesis and reveals a crucial pathway, VPS35-Lamp2a-α-synuclein, to prevent PD pathogenesis. Significance statement: VPS35 is a key component of the retromer complex that is essential for endosome-to-Golgi retrieval of membrane proteins. Mutations i…
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“At least five other genes that are associated with PD (but not LSDs) also affect CMA: LRRK2, UCHL2, VCP35, DJ-1, and SNCA, which encodes alpha-synuclein.149–153”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [152]
In the citing paper
“VPS35 deficiency alters the distribution of lysosome-associated membrane glycoprotein 2a (Lamp2a) in neurons19.”
From Retromer stabilization results in neuroprotection in a model of Amyotrophic Lateral Sclerosis (2020) · cites this paper as [19]
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Metadata
- Authors
- Tang, F.-L., Erion, J. R., Tian, Y., Liu, W., Yin, D.-M., Ye, J., Tang, B., Mei, L., & Xiong, W.-C.
- Affiliations
- Augusta University (US)
- Central South University (CN)
- Army Medical University (CN)
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2015-07-22
- Volume
- 35
- Issue
- 29
- Pages
- 10613-10628
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4510296
- OpenAlex
- W1953962861
- Cited by
- 269
- References
- 55
- Citations by year
- 2026: 14 · 2025: 10 · 2024: 28 · 2023: 28 · 2022: 19 · 2021: 34 · 2020: 39 · 2019: 19 · 2018: 26 · 2017: 22 · 2016: 26 · 2015: 4
- Type
- conference abstract
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Neuroscience (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX000838)
- National Institutes of Health (AG045781)
- National Institute on Aging (R01AG045781, RF1AG045781, AG045781)
- National Institute of Neurological Disorders and Stroke (P30NS055077)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- VPS35, Parkinson's disease, dopaminergic neurons, LAMP2A, chaperone-mediated autophagy, alpha-synuclein degradation, retromer complex, substantia nigra pars compacta, striatum
- MeSH terms
- Animals, Autophagy, Cells, Cultured, Golgi Apparatus, Mice, Inbred C57BL, Mice, Mutant Strains, Endosomes, Transfection, Blotting, Western, Mutagenesis, Site-Directed, Microscopy, Confocal, Parkinsonian Disorders, Protein Transport, Vesicular Transport Proteins, Mice, alpha-Synuclein, Lysosomal-Associated Membrane Protein 2, Dopaminergic Neurons, Real-Time Polymerase Chain Reaction
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