Pharmacological Modulation of Parkin Expression and Function to Attenuate Mitochondrial Dysfunction

Project: Research project

Description

Our aim is to identify drug-like molecules that increase the amount of the protein parkin in neuronal cells. Parkin is mutated in some people with Parkinsons disease (PD). Parkin removes damaged mitochondria (the powerhouses of the cells), which protect neurons from cell death. After developing new molecules that increase levels of parkin, our goal is to determine their therapeutic potential in PD models and to characterize how the drugs increase parkin levels. Mutations in genes encoding PINK1 and Parkin cause early onset familial PD. Consistent with genetic studies in Drosophila that indicate PINK1 functions upstream of Parkin in the same pathway, biochemical and cell biology studies show that PINK1 recruits Parkin to damaged mitochondria where Parkin can induce selective autophagy of damaged mitochondria. PINK1 is a kinase that has been shown to phosphorylate Parkin to trigger Parkin association with mitochondria. Parkin is an E3 ubiquitin ligase that ubiquitinates scores of substrates on mitochondria. These ubiquitinated substrates recruit adaptors such as p62 to mitochondria that are thought to be key for initiating autophagosome recognition of damaged mitochondria. Parkin activity through mitophagy or alternative pathways protects neurons from a variety of stresses. In vitro and in vivo studies indicate that increasing Parkin expression improves mitochondria quality control and protects dopaminergic neurons from mitochondrial stressors associated with aging. As aging is regarded as the primary risk factor for sporadic PD, it is logical the accumulation of dysfunctional mitochondria is an attractive avenue for therapeutic intervention. We seek to discover and validate drugs that boost Parkin expression level and ubiquitin ligase activity to reverse mitochondrial dysfunction and neuron loss in PD.
StatusFinished
Effective start/end date7/1/106/30/12

Funding

  • National Institutes of Health: $72,598.00

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ASJC

  • Medicine(all)