Researchers at the CUMC reveal the link between common genetic mutations in familial Parkinson's disease and brain cell damage.

Dr. Sulzer and his colleagues suspected that a gene called leucine-rich repeat kinase-2 (LRRK2) might be involved. LRRK2 mutations are the most common mutations to have been linked to Parkinson's. The current study aimed to determine how these mutations might lead to the accumulation of alpha-synuclein.
"We found that abnormal forms of LRRK2 protein disrupt a critical protein-degradation process in cells called chaperone-mediated autophagy," said Dr. Sulzer. "One of the proteins affected by this disruption is alpha-synuclein. As this protein starts to accumulate, it becomes toxic to neurons." Delving deeper, the researchers found that LRRK2 mutations interfere with LAMP-2A, a lysosome membrane receptor that plays a key role in lysosome function.
(Chaperone-mediated autophagy, or CMA, is responsible for transporting old or damaged proteins from the cell body to the lysosomes, where they are digested into amino acids and then recycled. In 2004, Dr. Sulzer and the current paper's other co-lead author, Ana Maria Cuervo, MD, PhD, professor of developmental & molecular biology, of anatomy & structural biology, and of medicine at Albert Einstein College of Medicine of Yeshiva University, showed that alpha-synuclein is degraded by the CMA pathway.)
"Now that we know this step that may be causing the disease in many patients, we can begin to develop drug treatments or genetic treatments that can enhance the digestion of these disease-triggering proteins, alpha-synuclein and LRRK2, or that remove alpha-synuclein," said Dr. Sulzer.
While LRRK2 mutations are the most common genetic cause of Parkinson's, it is too early to tell whether these findings, and therapies that might stem from them, would apply to patients with non-familial Parkinson's, the more common form of the disease. "Right now, all we can say is that it looks as though we've found a fundamental pathway that causes the buildup of alpha-synuclein in people with LRRK2 mutations and links these mutations to a common cause of the disease. We suspect that this pathway may be involved in many other Parkinson's patients," said Dr. Sulzer.
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Source-Eurekalert