Parkinson's Gene Discovery May Implicate Brain's Protein Disposal System in Other Neurodegenerative Diseases

September 1998

BETHESDA, Md. - Researchers at the National Institutes of Health (NIH), and their colleagues, have identified another gene that causes Parkinson's disease. The finding bolsters their hypothesis that defects in a pathway for disposing of flawed proteins are responsible not only for Parkinson's, but for several other late-onset, neurodegenerative disorders. The report is being published in the October 1st issue of Nature.

The paper describes two German siblings (brother and sister) with Parkinson's disease who also possess an alteration in the gene that produces ubiquitin carboxy-terminal hydrolase L1 (Uch-L1), a protein that is involved in the tagging of other proteins for routine disposal in the brain. "The significance of this paper is that it points to a particular pathway, as well as an array of possible changes that could go wrong in that pathway, in Parkinson's disease," said the paper's corresponding author Dr. Mihael Polymeropoulos of the National Human Genome Research Institute's (NHGRI's) Genetic Disease Research Branch.

In 1996, NHGRI scientists led the team of researchers who located a gene that causes some rare forms of familial Parkinson's disease. Until then, most experts believed the disease - which eventually strikes about 1 in 100 individuals - was most likely due exclusively to unknown environmental factors. In 1997, the researchers identified the alteration, which was in a gene that produces the protein alpha synuclein. The alteration may cause the protein to fold abnormally, thus forming a misshapen protein that is difficult to break down and dispose.

Alpha synuclein accumulates in the brain of all Parkinson's patients, even those without the alteration, and so does UCH-L1. This suggests that something is going wrong with the brain's method for disposing these proteins. The altered genes are responsible for only a tiny fraction of Parkinson's disease, which leads the researchers to believe there are other ways - probably many other ways, all of them still unknown - in which the brain's disposal system can fail.

There is a growing consensus among researchers studying Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), and other late-onset neurodegenerative diseases that they may all be looking at the same process: aggregation and accumulation of abnormal proteins. In each disease, the inclusions in the brain are different from each other and accumulate in different regions, and the constituent proteins are different (for example, beta amyloid in Alzheimer's and huntingtin in Huntington's disease). But the underlying pathological process in all of them is believed to be similar.

The process is the accumulation of abnormally folded proteins, which occurs either because of acquired or inherited defects in the ubiquitin-proteasome pathway. Proteasomes are large cylindrical molecules that grind up a cell's unwanted proteins and convert them to peptide fragments. But in the late-onset neurodegenerative diseases, something could go awry with the grinding process. The proteins being fed into the proteasome may be resistant to being degraded, perhaps because they are folded abnormally, and clog the proteasome. Or perhaps components of the proteasomes themselves may be dysfunctional.

"I would not be surprised if the ubiquitin-proteasome pathway is implicated in many other neurodegenerative disorders," Polymeropoulos said. "Last year's finding was one piece of a multiple piece puzzle in understanding Parkinson's disease. It is clear now that although the new finding represents another piece in that puzzle, and there may be 20 or 30 more."

NHGRI oversees the NIH's role in the Human Genome Project, an international research effort to develop tools for gene discovery.

Contact:
Jeff Witherly
NHGRI

Galen Perry
NHGRI

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Last Reviewed: February 28, 2012

Last updated: February 28, 2012