Clean-up snafu that kills brain cells in Parkinson's identified

Scientists have discovered how the most common genetic mutations in familial Parkinsons disease damage brain cells.

The discovery could also open up treatment possibilities for both familial Parkinsons and the more common form of Parkinsons that is not inherited, said researchers at Albert Einstein College of Medicine of Yeshiva University.

Parkinsons disease is a gradually progressing disorder of the nervous system that causes stiffness or slowing of movement.

The most common mutations responsible for the familial form of Parkinsons 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 hasnt been clear how LRRK2 mutations lead to the defining microscopic sign of Parkinsons: the formation of abnormal protein aggregates inside dopamine-producing nerve cells of the brain.

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 Parkinsons patients, said study leader Ana Maria Cuervo, MD, Ph.D., 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 Einstein.

The name for the disrupted disposal process is chaperone-mediated autophagy (the word autophagy literally means self-eating). It involves specialized molecules that guide old and damaged proteins to enzyme-filled structures called lysosomes; there the proteins are digested into amino acids, which are then recycled within the cell.

We showed that when LRRK2 inhibits chaperone-mediated autophagy, alpha-synuclein doesnt get broken down and instead accumulates to toxic levels in nerve cells, said Dr Cuervo.

The study involved mouse neurons in tissue culture from four different animal models, neurons from the brains of patients with Parkinsons with LRRK2 mutations, and neurons derived from the skin cells of Parkinsons patients via induced pluripotent stem (iPS) cell technology. All the lines of research confirmed the researchers discovery.

Were now looking at ways to enhance the activity of this recycling system to see if we can prevent or delay neuronal death and disease, said Dr Cuervo.

Weve started to analyze some chemical compounds that look very promising, she stated.

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Clean-up snafu that kills brain cells in Parkinson's identified