SNCA and LRKK2 Interaction

It is now over 16 years since my team reported the PD-causing role of a gene mutation, PARK1, in the alpha-synuclein protein (SNCA). So what have we learned since? If you do a search on PD and alpha-synuclein, you will get over 200,000 hits. Yet, here we are up to the discovery of PARK18 and still no miracle cure.

It turns out that the mutation in SNCA that we found in a large Italian family was originally introduced by Greek émigrés into Italy, but it remains a relatively infrequent cause of inherited PD. Then, in 2004, a mutation (PARK8) in the protein, leucine-rich repeat kinase 2 (LRKK2) was described and found to be a more common cause of PD. Known also as dardarin, LRKK2 can, like SNCA, form protein clumps inside brain cells.

But how do two disparate proteins cause a similar disease? Dr. Steven Finkbeiner’s group at Gladstone Institute of Neurological Disease at UCSF has begun to decipher this by using sophisticated imaging techniques to view the lifespan of single cells. Using cells from mice without SNCA and cells from PD patients with the most common LRKK2 mutation, they reported that the level of LRKK2 is what causes cell death, and that this level is dependent on SNCA.

Each of the steps that is clarified in the complicated pathway leading to PD opens new ways to approach potential treatment of this disease. Understanding the interaction of these two disparate PD-causing proteins, SNCA and LRKK2, is a very significant breakthrough that is key to clarifying that pathway.

For those of us who suffer from Parkinson disease, the hope is that these these findings bring us closer to developing effective treatment. As someone who was part of the team that set it in motion, I am excited to see a connection  established between “our” gene and the more common mutation.

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