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Funded Studies

Exploring the Mechanisms of Neuropathology in D620N VPS35 Knockin Mice

Study Rationale:
Recent findings indicate that mutations in the VPS35 gene cause a type of familial Parkinson's disease. Normally VPS35 is involved in the trafficking of protein cargo, but we don't yet know how VPS35 mutations affect the brain and lead to Parkinson's. We have developed a novel VPS35 model harboring a disease-linked mutation that we will use to explore ways VPS35 mutations might induce damage to brain cells.

We hypothesize that neurodegeneration in a VPS35 pre-clinical model may result from the abnormal activation of the Parkinson's-related protein LRRK2 and may also involve abnormal tau protein.

Study Design:
Our studies will evaluate the potential mechanisms involving VPS35, LRRK2 and abnormal tau. We will determine whether genetic deletion or pharmacological inhibition of LRRK2 can prevent or delay damage to brain cells in pre-clinical VPS35 models. To do this, we will cross VPS35 knockin models with LRRK2 knockout models or treat them with a LRRK2 kinase inhibitor. We will also determine whether abnormal tau protein contributes to neurodegeneration in VPS35 knockin models by crossing them with tau knockout mice.

Impact on Diagnosis/Treatment of Parkinson's disease:
Our studies will evaluate the role of VPS35 in Parkinson's-relevant models. This study will clarify the mechanism by which autosomal dominant mutations in VPS35 induce cellular damage in Parkinson's. It is anticipated that our findings will be relevant for understanding the molecular mechanism(s) underlying both familial and sporadic Parkinson's and may identify VPS35 as a new drug target.

Next Steps for Development:
Our studies may help to guide the development of future therapies targeting the effects of VPS35 genetic mutations.


  • Darren J. Moore, PhD

    Grand Rapids, MI United States

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