The HARPER Lab

Department of Cell Biology

Applying ubiquitin proteomics to diseases such as Parkinson’s Disease

The parkin-dependent ubiquitylome.

PARKIN is a Ubiquitin ligase that is mutated in early onset Parkinson’s Disease. In response to mitochondrial depolarization, PARKIN is recruited to the mitochondrial outer membrane (MOM) in a PINK1 kinase dependent manner. There, PARKIN ubiquitylates proteins on the MOM to regulate mitochondrial dynamics and the process of mitophagy, wherein mitochondria are targeted for autophagy. We applied quantitative diGLY proteomics to the problem of PARKIN substrate identification, thereby revealing the landscape of the PARKIN modified ubiquitylome - the collection of ubiquitylation sites in PARKIN-dependent ubiquitylation targets. This work provides a resource for the field and will enable an understanding of how PARKIN regulates mitochondrial function.

We are currently extending these studies to other quality control pathways including ALS.