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Parkinson’s Disease-Linked Mutations in VPS35 Induce Dopaminergic Neurodegeneration

Tsika, E; Glauser, L; Moser, R; Fiser, A; Daniel, G; Sheerin, U; Lees, A; Troncoso, J C; Lewis, P A; Bandopadhyay, R; Schneider, B L; Moore, D J


E Tsika

L Glauser

R Moser

A Fiser

G Daniel

U Sheerin

A Lees

J C Troncoso

P A Lewis

R Bandopadhyay

B L Schneider

D J Moore


Mutations in the vacuolar protein sorting 35 homolog (VPS35) gene at the PARK17 locus, encoding a key component of the retromer complex, were recently identified as a new cause of late-onset, autosomal dominant Parkinson's disease (PD). Here we explore the pathogenic consequences of PD-associated mutations in VPS35 using a number of model systems. VPS35 exhibits a broad neuronal distribution throughout the rodent brain, including within the nigrostriatal dopaminergic pathway. In the human brain, VPS35 protein levels and distribution are similar in tissues from control and PD subjects, and VPS35 is not associated with Lewy body pathology. The common D620N missense mutation in VPS35 does not compromise its protein stability or localization to endosomal and lysosomal vesicles, or the vesicular sorting of the retromer cargo, sortilin, SorLA and cation-independent mannose 6-phosphate receptor, in rodent primary neurons or patient-derived human fibroblasts. In yeast we show that PD-linked VPS35 mutations are functional and can normally complement VPS35 null phenotypes suggesting that they do not result in a loss-of-function. In rat primary cortical cultures the overexpression of human VPS35 induces neuronal cell death and increases neuronal vulnerability to PD-relevant cellular stress. In a novel viral-mediated gene transfer rat model, the expression of D620N VPS35 induces the marked degeneration of substantia nigra dopaminergic neurons and axonal pathology, a cardinal pathological hallmark of PD. Collectively, these studies establish that dominant VPS35 mutations lead to neurodegeneration in PD consistent with a gain-of-function mechanism, and support a key role for VPS35 in the development of PD.


Tsika, E., Glauser, L., Moser, R., Fiser, A., Daniel, G., Sheerin, U., …Moore, D. J. (2014). Parkinson’s Disease-Linked Mutations in VPS35 Induce Dopaminergic Neurodegeneration. Human Molecular Genetics, 23(17), 4621-4638.

Journal Article Type Article
Acceptance Date Apr 14, 2014
Publication Date Apr 15, 2014
Deposit Date Jan 17, 2020
Publicly Available Date Jan 20, 2020
Print ISSN 0964-6906
Publisher Oxford University Press
Peer Reviewed Peer Reviewed
Volume 23
Issue 17
Pages 4621-4638
Public URL


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