Mutant Parkinson's protein damages cells

Mutation in a single gene contributes to the abnormal build-up of protein present in the neurons of people with Parkinson's disease (PD), according to a new study by Hopkins researchers. Alterations in the gene's protein product, alpha-synuclein, appear to render neurons more susceptible to the damaging effects of age-related stress and, ultimately,?may lead to their premature death. PD is a degenerative disease of the nervous system, usually characterized by tremors, muscle rigidity and a general slowing of movement. While the exact cause of PD remains unclear, most scientists agree that both genes and environment play a role. Evidence in support of the genetic hypothesis is not hard to find. A study in 1997, for example, showed an unusually high prevalence of PD in?the small Italian village of Contursi Terme; one family had 60 cases spread over only six generations. By studying DNA samples from the affected villagers, researchers?pinpointed a mutation of?the alpha-synuclein gene as a factor?causing the?higher-than-expected?number of PD cases. Since then, two more kinds of mutations to the gene have been discovered in other families.Further research found that mutant alpha-synculein?is a major component of Lewy bodies, accumulations of protein in neurons that have classically been associated with?PD. Moreover, mutated copies of the alpha-synculein gene were shown to be passed down in an autosomal dominant fashion, meaning that one copy of the gene is sufficient to induce the formation of Lewy bodies and increase an individual's risk of acquiring PD. There's also some evidence to suggest that normal variation in levels of alpha-synculein between individuals contributes to this risk - even in people lacking the rare genetic mutations that cause heritable forms of PD, as in Contursi.Nonetheless, the molecular pathways by which alpha-synuclein operates on the molecular level to produce the startling physical impairments seen in PD has been uncertain. The Hopkins group, led by Wanli Smith and colleagues at the School of Medicine's Department of Psychiatry, sought to settle the case about alpha-synuclein's role in the diseased cells of PD. Specifically, the group wanted to see how turning on genes that produce alpha-synculein would affect a cell's development. To this end, they chose a special line of easily modifiable cells into which they inserted either the mutated or normal copy of the alpha-synculein gene. The gene was then, by means of a specialized genetic tool, "turned on." After a week of growing in a medium that mimicked the environmental conditions present in the brain, the team collected the cells and evaluated them.Contrary to the researchers' expectations, cells with the mutated gene did not die at a higher rate than those with a normal copy. Nonetheless, the team observed marked biochemical changes in the mutated group, with noticeable decreases in the activity of the proteasome, the cell's garbage disposal. As in your kitchen sink, build-up of waste isn't a good thing in cells. Inside a brain cell, banana peels and chicken fat are replaced by various proteins, such as alpha-synculein, which a malfunctioning proteasome is unable to degrade. Accumulating proteins usually lead to cell death. Within the mutant group, the team also observed increases in reactive oxygen species (ROS). While normally critical to proper intercellular signaling, abnormally high ROS levels have been linked to many age-related neurological diseases. When in abundance, ROS wreaks general havoc on the cell, damaging DNA and degrading amino acids. Because ROS levels tend to increase as an individual gets older, many scientists theorize that ROS activity is the basis for aging and age-related diseases, including Parkinson's. Further research is required to determine exactly how mutated alpha-synculein leads to proteasome malfunction and how that impairment converges with the harmful effects of ROS to give rise to Parkinson's.