Einstein Researchers Discover Important Clue to the Cause of Parkinson's Disease 2 January 2008

Einstein researchers discover important clue to the cause of Parkinson's disease 2 January 2008

A glitch in the mechanism by which cells recycle at how several different modified forms of alpha- damaged components may trigger Parkinson’s synuclein affected autophagy in vitro and in tissue disease, according to a study by scientists at the culture. One particular modification of alpha- Albert Einstein College of Medicine of Yeshiva synuclein was found to interfere with autophagy: University. The research, which appears in the the compound created by the interaction of alpha- January 2 advance online issue of The Journal of synuclein with dopamine, the main neurotransmitter Clinical Investigation, could lead to new strategies produced by the nerve cells damaged in for treating Parkinson’s and other Parkinson’s disease. neurodegenerative diseases. “Alpha-synuclein molecules modified by dopamine All cells depend on a surveillance system known bound tightly to the lysosomal membrane, but they as autophagy (which literally means “self eating”) got stuck there and weren’t effectively transported to digest and recycle the damaged molecules that into the lysosome,” says Dr. Cuervo. As a result, arise as cells age. In autophagy, defective proteins the alpha-synuclein molecules altered by dopamine and other molecules are transported to membrane- were poorly degraded, and the presence of these bound sacs called lysosomes. After attaching to molecules on the lysosomal membranes interfered the lysosomal membrane, the molecules enter the with autophagic digestion of other compounds as lysosome, where they are digested by enzymes. well. This cleanup process may be particularly important for nerve cells, which generate defective molecules “We propose that inhibition of autophagy caused more rapidly than most other types of cells. When by dopamine’s alteration of alpha-synuclein could autophagy is impaired, toxic compounds can explain the selective death of dopamine-producing accumulate and cause cell death. nerve cells in Parkinson’s disease,” says Dr. Cuervo, who notes that interference with autophagy “It is widely suspected that accumulation of a has also been implicated in other particular protein, known as alpha-synuclein, within neurodegenerative diseases including Alzheimer’s. affected nerve cells of Parkinson’s disease patients contributes to the death of these cells,” “By devising strategies for boosting autophagy in says Dr. Ana Maria Cuervo, senior author of the nerve cells or suppressing the chemical reactions article and associate professor of anatomy & that interfere with the autophagy—by lowering alpha structural biology at Einstein. synuclein expression, for example--we may be able to treat patients afflicted with these conditions,” she Dr. Cuervo previously showed that mutant forms of says. alpha-synuclein—found in the five to 10 percent of patients who have familial Parkinson’s Source: Albert Einstein College of Medicine disease—are poorly digested via autophagy and also block the breakdown of other substances. While these alpha-synuclein mutations are rare, other modifications of alpha- synuclein—phosphorylated and oxidized forms, for example—can be found in the brains of all Parkinson’s disease patients.

In this study, Dr. Cuervo and her colleagues looked

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