Key Parkinson's clue could be protein aggregate

November 3, 2010 By Anne Ju, Cornell University
Transmission electron micrographs of classically rigid amyloid fibers and other, differently shaped aggregates formed from the Parkinson's disease-associated protein alpha-synuclein. The study of alternative aggregation pathways of alpha-synuclein may be crucial for understanding the initiation of the disease.

( -- Proteins perform almost every function our bodies require for life. But, they also can misbehave in myriad ways. By retracing the history of each abnormal reaction, biochemists aim to determine the events that lead to disease and to intervene in the process.

Collaborative research between Ithaca-based Cornell applied physicists and biochemists at Weill Cornell Medical College has yielded new clues into what happens when the Parkinson's disease-associated alpha-synuclein undergoes abnormal aggregation. These findings are published in the Nov. 2 edition of (online Oct. 14).

patients have dense lesions in their midbrains called Lewy bodies, which involve aggregates of alpha-synuclein. But it is still unclear whether Lewy bodies are a symptom of the disease or are themselves responsible for cell death. Many researchers surmise that smaller clusters (known as oligomers or aggregates) of alpha-synuclein protein could be responsible for initiating neurodegeneration.

The Cornell group, led by applied and engineering physics professor Watt W. Webb and Weill Cornell biochemistry professor David Eliezer, aimed to shed light on structural changes in alpha-synuclein. Using chemical solutions of fluorinated alcohol to trigger protein structural transitions, the researchers observed the formation of irregular, helical aggregates that may be similar to formations in the brain of Parkinson's disease patients. These structures, some long and thin, and others inter-wound or spooled, could suggest alternative pathways to alpha-synuclein aggregation in the brain.

"These ringlike annular aggregates have been seen with before, and people have been interested in them for a long time," said Valerie Anderson, first author and a graduate student in Webb's lab. The research shows that the aggregates maybe involved in infiltrating healthy cells and causing disease, which could result in toxicity. (See accompanying electron nanoscopic images.)

The new Cornell experiments paint stunning visual evidence of a wide array of protein aggregates with varying molecular structures, some of which might be key to understanding Parkinson's disease. In addition, the researchers identified early events in the assembly of these structures. By examining the interaction of types of polarized light with the alpha-synuclein protein, they observed rearrangements of the protein on the molecular level prior to aggregation. Additional changes in the molecular conformation occurred when the proteins stuck together; alpha-synuclein adopts a helical structure that converts to an aligned, sheetlike molecular assembly early in the aggregation process.

Understanding disease is like solving a mystery -- a million clues yield nothing, but the right one could lead to new treatments. These latest results shed light on early events that occur when behaves badly, although more research must be done to determine whether similar events take place in the brains of Parkinson's disease patients.

The researchers made use of microscopy and spectroscopy equipment at the Cornell Center for Materials Research, which is supported by the National Science Foundation. The research was also funded by the National Institutes of Health and the NSF Science and Technology Center program.

Explore further: How the pathology of Parkinson's disease spreads

Related Stories

How the pathology of Parkinson's disease spreads

July 27, 2009

( -- Accumulation of the synaptic protein alpha-synuclein, resulting in the formation of aggregates called Lewy bodies in the brain, is a hallmark of Parkinson's and other related neurodegenerative diseases. ...

Research reveals early steps in Parkinson's pathology

April 6, 2010

Although the cause of Parkinson's disease remains a mystery, scientists now have a better understanding of the earliest stages of abnormal aggregation of a key disease-associated protein. The research, published by Cell Press ...

Lessons from yeast: A possible cure for Parkinson's disease?

August 14, 2008

Parkinson disease (PD) is a debilitating and lethal neurodegenerative disease, for which there is currently no cure. It is caused by the progressive loss of nerve cells that produce the chemical dopamine and is characterized ...

Toxicity mechanism identified for Parkinson's disease

January 2, 2009

Neurologists have observed for decades that Lewy bodies, clumps of aggregated proteins inside cells, appear in the brains of patients with Parkinson's disease and other neurodegenerative diseases.

Yeast holds clues to Parkinson's disease

September 9, 2010

Yeast could be a powerful ally in the discovery of new therapeutic drugs to treat Parkinson's disease says a scientist presenting his work at the Society for General Microbiology's autumn meeting in Nottingham today.

Recommended for you

Engineers test drug transfer using placenta-on-a-chip

February 16, 2018

Researchers at the University of Pennsylvania's School of Engineering and Applied Science have demonstrated the feasibility of their "organ-on-a-chip" platform in studying how drugs are transported across the human placental ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.