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Efficacy of PRKN Gene Delivery toward Mitigation of Alpha-synuclein-induced Degeneration

Study Rationale:
Genetic mutations that cause the functional loss of the PRKN gene and its corresponding protein, parkin, can cause early-onset Parkinson’s disease (PD). Regardless of the cause, genetic or unknown, nearly all cases of PD show aggregates of the protein alpha-synuclein and loss of dopamine-producing cells in the brain. We will explore if gene delivery of PRKN to the brains of Parkinson’s models can prevent alpha-synuclein aggregation and loss of dopamine-producing cells. The data from these studies may impact therapeutic approaches for both genetic and non-genetic forms of PD.

We hypothesize that increasing parkin protein levels can protect against alpha-synuclein pathology and loss of dopamine neurons.

Study Design:
We will use viral vectors (tools to deliver genetic material into a cell) to increase expression of PRKN in part of the brain called the substantia nigra in models with genetic mutations linked to Parkinson’s disease. Then we will determine the extent to which activated or inactivated forms of parkin can protect against PD-relevant neuropathology and neurodegeneration induced by injecting thin fibers (fibrils) of alpha-synuclein.

Impact on Diagnosis/Treatment of Parkinson’s Disease:
Understanding the mechanisms by which parkin protein can provide a therapeutic benefit in models is a first step toward translating this therapeutic strategy for humans. Additionally, readouts from the tools and assays we use in this project may be useful biomarkers for clinical studies and thus, in themselves, represent a potential impact in monitoring the disease process in humans.

Next Steps for Development:
Successful completion of these studies will provide key data to support and guide the development of neuroprotective therapies based on increasing parkin activity. These studies will also help fill critical gaps in understanding why PRKN mutations cause early-onset PD and the degree to which parkin-mediated neuroprotection is dependent upon the PINK1 gene, mutations in which are also causally linked to early-onset PD. These questions are important to answer because parkin is thought to function in the same pathway as PINK1, but the optimal target for PD therapeutic development remains uncertain.


  • Jennifer A. Johnston, PhD

    Mill Valley, CA United States

  • Deniz Kirik, MD, PhD

    Lund Sweden

  • Matthew S. Goldberg, PhD

    Birmingham, AL United States

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