SNCA and LRKK2 Interaction
In 1997, when my team reported the PD-causing role of a gene mutation, PARK1, in the alpha-synuclein protein (SNCA) it was heralded by a press release at the Washington DC Press Club and touted in newspapers, including the NY Times. When SNCA was found to be the primary component of the protein clumps called Lewy bodies that are found inside PD cells, hopes were high for an immediate understanding of exactly how it caused PD.
That was perhaps as naïve as when, in 1985, geneticists thought identifying the cystic fibrosis-causing gene would lead immediately to a treatment for the disease. Almost 30 years later, while progress had been made treating CF, no magic bullet has been found. This is because pathways of human disease are extremely complicated.
It is now over 16 years since we discovered PARK1. 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. Traditional tools have only allowed researchers to monitor cell death outcomes in groups of cells. By using sophisticated imaging techniques to view the lifespan of single cells, Dr. Finkbeiner was able to separate out the contribution of different factors to cell death.
Using cells from mice without SNCA and cells from PD patients with the most common LRKK2 mutation, they reported in The Journal of Neuroscience [Jan 8, 2014-34(2):418-433] 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.