Loss of function mutations in either of the genes PINK1 or parkin are associated with autosomal recessive parkinsonism in humans. It is known that these two genes are linked in a single genetic pathway that normally prevents age-dependent mitochondrial dysfunction in Drosophila models. PINK1, which is a mitochondrial kinase has also been shown to support the recruitment of parkin to damaged or depolarized mitochondria. Once recruited to damaged organelles, parkin promotes their turnover via mitophagy, a specialized form of autophagy that acts as a form of mitochondrial quality control. Although several publications have outlined some of the essential molecules involved in PINK1-dependent parkin recruitment and subsequent mitophagy, many details are still unclear. For example, what occurs in depolarized mitochondria to trigger PINK1 activation is poorly understood.
The aim of this project is to understand the molecular basis of the relationship between PINK1 and parkin. To this end, we recently have completed a large shRNA screen against depolarization-induced parkin relocalization to find novel participants in this process. We were able to recover PINK1, showing that the screen worked, and are now validating additional genes. To date we have been able to confirm at least one other gene as well as PINK1, which happens to also be a mitochondrial protein. Functional assays in cell lines and in neurons suggest that this protein is upstream of PINK1 genetically although the mechanism by which it promotes PINK1 recruitment is still under investigation.
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