Novel Mitophagy Regulators
The Translational Cell Biology of Parkinson's Disease Lab research team is working with Owen A. Ross, Ph.D., to dissect the genetic architecture of early-onset Parkinson's disease (EOPD) and mitophagy through an integrated functional-genomics approach. The lab team performed a two-tiered, cell-based screening of functionally related sets of genes or entire genome-wide libraries to identify novel positive or negative regulators of the PINK1-PRKN (Parkin) pathway.
Using a newly developed bioinformatic pipeline, identified modifiers are overlaid and compared with whole-genome sequencing data derived from people with EOPD. Novel sequence variants in the highlighted genes are then structurally analyzed, functionally validated in cells and sorted according to their roles along the sequence of mitophagy. In all, this project will uncover novel therapeutic targets that are key regulators of mitophagy and genes involved in EOPD, similar to PINK1 and Parkin as well as other neurodegenerative disease genes that have already been linked to this pathway.
- Fiesel FC, Moussaud-Lamodière EL, Ando M, Springer W. A specific subset of E2 ubiquitin-conjugating enzymes regulate Parkin activation and mitophagy differently. Journal of Cell Science. 2014; doi:10.1242/jcs.147520.
- Kim J, Fiesel FC, Belmonte KC, Hudec R, Wang WX, Kim C, Nelson PT, Springer W, Kim J. miR-27a and miR-27b regulate autophagic clearance of damaged mitochondria by targeting PTEN-induced putative kinase 1 (PINK1). Molecular Neurodegeneration. 2016; doi:10.1186/s13024-016-0121-4.