Mechanism that leads to sporadic Parkinson's disease identified

September 25, 2012

Researchers in the Taub Institute at Columbia University Medical Center (CUMC) have identified a mechanism that appears to underlie the common sporadic (non-familial) form of Parkinson's disease, the progressive movement disorder. The discovery highlights potential new therapeutic targets for Parkinson's and could lead to a blood test for the disease. The study, based mainly on analysis of human brain tissue, was published today in the online edition of Nature Communications.

Studies of rare, familial (heritable) forms of Parkinson's show that a protein called alpha-synuclein plays a role in the development of the disease. People who have of the alpha-synuclein gene produce excess alpha-synuclein protein, which can damage neurons. The effect is most pronounced in dopamine neurons, a population of in the that plays a key role in controlling normal movement and is lost in Parkinson's. Another key feature of Parkinson's is the presence of excess alpha-synuclein aggregates in the brain.

As the vast majority of patients with Parkinson's do not carry rare familial mutations, a key question has been why these individuals with common sporadic Parkinson's nonetheless acquire excess alpha-synuclein protein and lose critical , leading to the disease.

Using a variety of techniques, including and gene-network mapping, the CUMC researchers discovered how common forms of alpha-synuclein contribute to sporadic Parkinson's. "It turns out multiple different alpha-synuclein transcript forms are generated during the initial step in making the disease protein; our study implicates the longer transcript forms as the major culprits," said study leader Asa Abeliovich, MD, PhD, associate professor of pathology and neurology at CUMC. "Some very common genetic variants in the alpha-synuclein gene, present in many people, are known to impact the likelihood that an individual will suffer from sporadic Parkinson's. In our study, we show that people with 'bad' variants of the gene make more of the elongated alpha-synuclein transcript forms. This ultimately means that more of the disease protein is made and may accumulate in the brain."

"An unusual aspect of our study is that it is based largely on detailed analysis of actual patient tissue, rather than solely on animal models," said Dr. Abeliovich. "In fact, the longer forms of alpha-synuclein are human-specific, as are the disease-associated genetic variants. Animal models don't really get Parkinson's, which underscores the importance of including the analysis of human brain tissue."

"Furthermore, we found that exposure to toxins associated with Parkinson's can increase the abundance of this longer transcript form of alpha-synuclein. Thus, this mechanism may represent a common pathway by which environmental and genetic factors impact the disease," said Dr. Abeliovich.

The findings suggest that drugs that reduce the accumulation of elongated alpha-synuclein transcripts in the brain might have therapeutic value in the treatment of Parkinson's. The CUMC team is currently searching for drug candidates and has identified several possibilities.

The study also found elevated levels of the alpha-synuclein elongated transcripts in the blood of a group of patients with sporadic Parkinson's, compared with unaffected controls. This would suggest that a test for may serve as a biomarker for the disease. "There is a tremendous need for a biomarker for Parkinson's, which now can be diagnosed only on the basis of clinical symptoms. The finding is particularly intriguing, but needs to be validated in additional patient groups," said Dr. Abeliovich. A biomarker could also speed clinical trials by giving researchers a more timely measure of a drug's effectiveness.

Explore further: SUMO defeats protein aggregates that typify Parkinson's disease

More information: "Alternative alpha-synuclein transcript usage as a convergent mechanism in Parkinson's disease pathology," Nature Communications, 2012.

Related Stories

SUMO defeats protein aggregates that typify Parkinson's disease

July 11, 2011
A small protein called SUMO might prevent the protein aggregations that typify Parkinson's disease (PD), according to a new study in the July 11, 2011, issue of The Journal of Cell Biology.

How Parkinson's disease starts and spreads

April 16, 2012
Injection of a small amount of clumped protein triggers a cascade of events leading to a Parkinson's-like disease in mice, according to an article published online this week in the Journal of Experimental Medicine.

Recommended for you

Tapeworm drug could lead the fight against Parkinson's disease

December 12, 2017
Researchers at Cardiff University, in collaboration with the University of Dundee, have identified a drug molecule within a medicine used to treat tapeworm infections which could lead to new treatments for patients with Parkinson's ...

High-intensity exercise delays Parkinson's progression

December 11, 2017
High-intensity exercise three times a week is safe for individuals with early-stage Parkinson's disease and decreases worsening of motor symptoms, according to a new phase 2, multi-site trial led by Northwestern Medicine ...

Changes in diet may improve life expectancy in Parkinson's patients

November 24, 2017
New research from the University of Aberdeen shows that weight loss in people with Parkinson's disease leads to decreased life expectancy, increased risk of dementia and more dependency on care.

Good cells gone bad: Scientists discover PINK-SNO

November 21, 2017
A new study from The Scripps Research Institute (TSRI) is the first to show precisely how a process in nerve cells called the S-nitrosylation (SNO) reaction—which can be caused by aging, pesticides and pollution—may contribute ...

Genetic defects in the cell's 'waste disposal system' linked to Parkinson's disease

November 14, 2017
An international study has shed new light on the genetic factors associated with Parkinson's disease, pointing at a group of lysosomal storage disorder genes as potential major contributors to the onset and progression of ...

Parkinson's disease: A looming pandemic

November 13, 2017
New research shows that the number of people with Parkinson's disease will soon grow to pandemic proportions. In a commentary appearing today in the journal JAMA Neurology, University of Rochester Medical Center neurologist ...

0 comments

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.