NEW YORK (Reuters Health) - Cell biologists are closing in on the pathogenic processes that underlie the neurodegeneration associated with familial Parkinson’s disease (PD), according to a report in the August 27th issue of Science.
In familial PD, mutated alpha-synuclein accumulates within the cell, lead author Dr. Ana Maria Cuervo, of Albert Einstein College of Medicine in Bronx, New York, told Reuters Health.
“We wanted to know why this protein accumulates and is not removed,” she said. “We realized that not only is it not removed, it blocks the removal of other proteins that are normally degraded within the lysosome, and that is what eventually kills the neuron.”
She explained that the lysosome has two pathways for degrading damaged proteins, one called “chaperone-mediated autophagy” (CMA), in which a chaperone-substrate complex binds to the lysosomal membrane receptor. The substrate proteins, including wild-type alpha-synuclein, are then translocated into the lumen of the lysosome for enzymatic degradation.
Her group found that aberrant alpha-synuclein binds more tightly to the lysosome receptors but is then poorly internalized. As a result, other damaged cytosolic proteins that are normally taken up by the lysosome and degraded cannot bind to the lysosomal membrane receptor.
Early in this process, another, less selective pathway that degrades proteins, called macroautophagy, is activated. In this process, large regions of cytosol are engulfed and degraded. The researchers found that, although wild-type alpha-synuclein is not subject to macroautophagy, the mutated forms are. Under these conditions, however, macroautophagy cannot maintain normal rates of protein degradation.
“When synuclein blocks one pathway, the other compensates for a while, but over time it gets overwhelmed,” Dr. Cuervo said. That is one reason why patients “get worse and worse as they age.”
“We hope that we can find a way to stimulate the removal system that the mutant alpha-synuclein blocks,” she concluded. “If we can do so early enough in the disease process and prevent toxic protein accumulation, hopefully we will ameliorate symptomatology of the disease.”
Source: Science 2004;305:1292-1295. [ Google search on this article ]
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