New Insight into Proteins and Parkinson's

New research into the role of two enzymes in cell signaling has shed new light on early onset Parkinson’s. While it has been known for a while that two enzymes, PINK1 and PARKIN, are implicated in Parkinson’s, the research of Ordureau et al. has illuminated the specific mechanism of the malfunction.

Parkinson’s is a neurodegenerative disease characterized by mitochondrial malfunction. The mitochondria are a major source of energy in the cell. When the mitochondria are damaged so that they work improperly, they generate chemicals that kill the cell. In a healthy individual, damaged mitochondria are marked for degradation. The degradation keeps the cell healthy.

In Parkinson’s, damaged mitochondria are not properly marked for degradation, causing neuronal cell death. The loss of neurons means that affected individuals are not generating enough of the neurotransmitter dopamine for motor function.

So where do the enzymes PINK1 and PARKIN come into the picture? These enzymes play a crucial role in cell health because they attach the protein ubiquitin to the surface of mitochondria to signal damage and future degradation. In order for a damaged mitochondrion to be degraded, enough ubiquitin must be attached to its surface in order to attract more proteins to break it down. PINK1 identifies damaged mitochondria and attracts PARKIN to them. PARKIN attaches ubiquitin to the mitochondria. The interesting thing about this mechanism is that once ubiquitin is attached to the mitochondria, it further accentuates the role of PARKIN so that even more ubiquitin is attached, ensuring that the damaged mitochondria will be degraded. This is called a ‘feed-forward’ mechanism.

This research is significant because even though PINK1 and PARKIN have been known to play a role in Parkinson’s the specifics of their role are only just now understood. For individuals with early onset Parkinson’s, the dysfunction of PINK1 and PARKIN means that damaged mitochondria are not being degraded, leading to cell death and the progression of Parkinson’s. With more specific details about the way that these two enzyme work, new avenues for treatment can be investigated.

Reference: Ordureau, Alban, et al. 2014 Oct. Quantitative Proteomics Reveal a Feedforward Mechanism for Mitochondrial PARKIN Translocation and Ubiquitin Chain Synthesis. Molecular Cell. http://www.cell.com/molecular-cell/abstract/S1097-2765%2814%2900714-X