Updated on 4 March 2013
Researchers at Albert Einstein College of Medicine of Yeshiva University, US, find that genetic mutations in leucine-rich repeat kinase-2 (LRRK2) lead to familial Parkinson's disease
Singapore: Researchers at Albert Einstein College of Medicine of Yeshiva University, US, have discovered how the most common genetic mutations in familial Parkinson's disease damage brain cells. The most common mutations responsible for the familial form of Parkinson's disease affect a gene called leucine-rich repeat kinase-2 (LRRK2).
The mutations cause the LRRK2 gene to code for abnormal versions of the LRRK2 protein. But it hasn't been clear how LRRK2 mutations lead to the defining microscopic sign of Parkinson's: the formation of abnormal protein aggregates inside dopamine-producing nerve cells of the brain. The study involved mouse neurons in tissue culture from four different animal models, neurons from the brains of patients with Parkinson's with LRRK2 mutations, and neurons derived from the skin cells of Parkinson's patients via induced pluripotent stem (iPS) cell technology. All the lines of research confirmed the researchers' discovery.
"Our study found that abnormal forms of LRRK2 protein disrupt an important garbage-disposal process in cells that normally digests and recycles unwanted proteins including one called alpha-synuclein - the main component of those protein aggregates that gunk up nerve cells in Parkinson's patients," said study leader Dr Ana Maria Cuervo, professor of developmental and molecular biology, of anatomy and structural biology, and of medicine and the Robert and Renee Belfer chair for the study of neurodegenerative diseases at the college.
Dr Cuervo, "We showed that when LRRK2 inhibits chaperone-mediated autophagy, alpha-synuclein doesn't get broken down and instead accumulates to toxic levels in nerve cells. We're now looking at ways to enhance the activity of this recycling system to see if we can prevent or delay neuronal death and disease. We've started to analyze some chemical compounds that look very promising."
Dr Cuervo is credited with discovering chaperone-mediated autophagy. She has published extensively on autophagy and its role in numerous diseases, such as cancer and Huntington's disease, and its role in age-related conditions, including organ decline and weakened immunity. Dr Cuervo is co-director of Einstein's Institute of Aging Research.