Paper in The Journal of Clinical Investigation describes how modified alpha-synuclein disrupts autophagy, which may cause death of dopamine-producing nerve cells.
Improper functioning during autophagy may trigger Parkinson’s disease, according to scientists at the Albert Einstein College of Medicine of Yeshiva University. The culprit they say is the compound formed through the interaction of dopamine with a protein already implicated in the disease.
“It is widely suspected that accumulation of a particular protein, known as alpha-synuclein, within affected nerve cells of Parkinson’s disease patients contributes to the death of these cells,” says Ana Maria Cuervo, M.D., Ph.D., senior author of the article and associate professor of anatomy & structural biology.
She has previously shown that mutant forms of alpha-synuclein, which are found in the five to 10 percent of those with familial Parkinson’s, 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, such as phosphorylated and oxidized forms, can be found in the brains of all Parkinson’s disease patients. In the current study, Dr. Cuervo’s team looked at how several modified forms of alpha-synuclein affected autophagy in vitro and in tissue culture.
They report that the compound created by the interaction of alpha-synuclein with dopamine was found to interfere with autophagy. When autophagy works normally, defective proteins and other molecules attach to the lysosomal membrane and then enter the lysosome, where they are digested by enzymes.
Dr. Cuervo observed, however, that “Alpha-synuclein molecules modified by dopamine bound tightly to the lysosomal membrane, but they got stuck there and weren’t effectively transported into the lysosome.” As a result, the alpha-synuclein molecules altered by dopamine were poorly degraded. Their presence on the lysosomal membranes interfered with autophagic digestion of other compounds as well.
“We propose that inhibition of autophagy caused by dopamine’s alteration of alpha-synuclein could explain the selective death of dopamine-producing nerve cells in Parkinson’s disease,” explains Dr. Cuervo, who notes that interference with autophagy has also been implicated in other neurodegenerative diseases including Alzheimer’s.
This research also included collaborators from Columbia University, the University of Pennsylvania, and Harvard Medical School. The study appeared in the January 2 advance online issue of The Journal of Clinical Investigation.