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Funded Studies

VPS35 as a Novel Target for Parkinson's Disease

Objective/Rationale:

Mutations in the VPS35 gene were recently identified as a cause of autosomal dominant familial Parkinson's disease (PD). How mutations in VPS35 precipitate the demise of dopaminergic neurons in PD is not yet known. Accordingly, we will develop novel models in cultured neurons and in rodents using viral-mediated gene transfer to explore the mechanism through which missense mutations induce neuronal damage.

Project Description:

Our studies will explore how or whether disease-associated missense mutations in VPS35 induce neuronal degeneration in neuronal culture and pre-clinical models. Since VPS35 mutations are inherited in an autosomal dominant manner this implies that they could act through a gain-of-function mechanism or potentially through a mechanism involving dominant-negative or haploinsufficient effects. To distinguish between these possibilities, we will develop viral vectors for the overexpression of human VPS35 variants and for gene silencing using short hairpin RNAs. These viral vectors will be employed to modulate VPS35 expression in primary midbrain cultures to evaluate the impact on dopaminergic neuronal integrity and viability. Viral vectors will also be delivered to the nigrostriatal dopaminergic pathway of rats to evaluate the age-dependent development of PD-related neurodegeneration, neuropathology and motor impairments.

Relevance to Diagnosis/Treatment of Parkinson's Disease:

Our studies will formally evaluate the role of a potential new target, VPS35, in PD-relevant models. This study will clarify the mechanism by which autosomal dominant mutations in VPS35 induce neurodegeneration in PD. Our findings may identify VPS35 as new drug target for therapeutic intervention in PD. It is anticipated that our findings will be relevant for understanding the molecular mechanism(s) underlying both familial and sporadic PD.

Anticipated Outcome:

This project will determine how VPS35 mutations induce PD-relevant phenotypes in neuronal culture and pre-clinical animal models. Our studies will help to guide the development of future therapies for PD based upon modulating VPS35-dependent neurodegeneration.

Final Outcome

We have evaluated the impact of modulating VPS35 gene expression on the development of neurodegenerative phenotypes in primary neuronal cultures and the nigrostriatal dopaminergic pathway of adult rats. Our goal is to determine the mechanism of action of the dominant PD-associated mutation, D620N, and develop new animal models of VPS35-linked PD. We have demonstrated that the viral-mediated expression of human VPS35 variants in neuronal cultures induces cell death, impaired neurite outgrowth and increases the susceptibility of neurons to cellular stress. In a viral-mediated gene transfer rat model, the expression of D620N VPS35 in the substantia nigra induced dopaminergic neuronal degeneration and axonal pathology, thereby recapitulating one of the pathological hallmarks of PD. Our study suggests that dominant mutations in VPS35 cause PD consistent with a gain-of-function mechanism. Our new VPS35 animal model of PD will prove useful for understanding disease mechanisms and for evaluating therapeutic strategies targeting VPS35.


Researchers

  • Darren J. Moore, PhD

    Grand Rapids, MI United States


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