Identifying a genetic mutation behind sporadic Parkinson's disease

April 20, 2016, Whitehead Institute for Biomedical Research
Immunohistochemistry for alpha-synuclein showing positive staining (brown) of an intraneural Lewy-body in the Substantia nigra in Parkinson's disease. Credit: Wikipedia

Using a novel method, Whitehead Institute researchers have determined how a non-coding mutation identified in genome-wide association studies (GWAS) can contribute to sporadic Parkinson's disease (PD). The approach could be used to analyze GWAS results for other sporadic diseases with genetic causes, such as multiple sclerosis, diabetes, and cancer.

"This is really the first time we've gone from risk variants highlighted by GWAS to a mechanistic and molecular understanding—right down to the nucleotide—of how a mutation can contribute to the risk of developing disease," says Whitehead Founding Member Rudolf Jaenisch, who is also a professor of biology at MIT.

About 90% of PD cases are sporadic; that is, caused by complex interactions between environmental and common genetic risk factors. Because scientists have had difficulty analyzing these interactions, most research has focused on rare familial forms of the disease. GWAS, which identify common mutations that increase the risk to develop a particular condition, have been used to study sporadic PD, and other complex conditions, with limited success.

GWAS are akin to genomic treasure maps bearing hundreds or thousands of X's marking the general locations of mutations that could be risk factors for a given condition. However, GWAS do not reveal the specific locations of potentially pathogenic mutations, nor do they indicate how an X on a genomic map contributes, if at all, to a disease. For example, in sporadic PD, multiple GWAS point to the alpha-synuclein gene (SNCA) as one of the strongest risk loci in patients' genomes, yet GWAS contain little information regarding the mechanism of how this gene is dysregulated in sporadic PD patients.

To see if distant gene regulatory elements on the same chromosome carrying SNCA could affect cellular levels of alpha-synuclein, a team of researchers led by Frank Soldner, a senior researcher in the Jaenisch lab, investigated two GWAS-flagged risk variants located in a putative SNCA enhancer. Their results are described online this week in the journal Nature.

The team used clustered regularly-interspaced short palindromic repeats (CRISPR)/Cas9 to edit the mutations into isogenic human pluripotent stem cells. By altering the genetic variant on only one chromosome, the other chromosome remains unchanged and acts as an internal control. This method allows the scientists to measure very subtle effects with very high confidence, while eliminating the effect of any genetic or epigenetic modifications and cell culture related variations that could occur during the experiment.

"Our method addresses an essential shortcoming of GWAS—using the correlations produced by GWAS, you cannot distinguish the effect between two variants that are very close together in the genome," says Soldner, who is the lead author of the Nature paper. "Such physical proximity means that they will always co-segregate during inheritance, which is why we had to do what we did—modify and analyze each variant independently while keeping the rest of the genome completely constant."

After differentiating the cells into neurons, the scientists noted the changes in SNCA expression. Although one of the mutations has no effect, the other, which switches one nucleotide from an A to a G, slightly but significantly boosts alpha-synuclein production. When compared to the enhanced alpha-synuclein production in the familial form of the disease, the modest effect created by the A to G mutation would be sufficient over a lifetime to increase the risk of PD, according to Soldner.

To see how the mutation affects alpha-synuclein production, the researchers identified two transcription factors that bind to the enhancer that carries this mutation. When the enhancer is not mutated, the transcription factors bind to it, which suppresses SNCA. If the enhancer has the G mutation, the are unable to bind to the enhancer, and SNCA is activated.

Most genetic conditions are sporadic and caused by a combination of mutations.

Jaenisch says that the method that identified the single point mutation in SNCA's enhancer could be used to pinpoint additional pathogenic genes for sporadic PD and sift through the GWAS hits for other diseases, including Alzheimer's disease, cancer, diabetes, and .

Explore further: Genome studies can help identify lifestyle risks for diseases

More information: Frank Soldner et al, Parkinson-associated risk variant in distal enhancer of α-synuclein modulates target gene expression, Nature (2016). DOI: 10.1038/nature17939

Related Stories

Genome studies can help identify lifestyle risks for diseases

February 12, 2016
Genome wide association studies (GWAS) scan the entire genome in order to pinpoint genetic variants associated with a particular disease. The technique is employed to identify biological pathways - the series of actions and ...

Study uncovers genetic variation that predicted type and rate of physical decline in patients with Parkinson's disease

April 14, 2016
Researchers at the Perelman School of Medicine at the University of Pennsylvania and other institutions have uncovered a site of genetic variation that identified which patients with Parkinson's disease are more likely to ...

New strategy for mapping regulatory networks associated with multi-gene diseases

April 23, 2015
Scientists at the University of Massachusetts Medical School have applied a powerful tool in a new way to characterize genetic variants associated with human disease. The work, published today in Cell, will allow scientists ...

Study investigates genetic variants' role in increasing Parkinson's disease risk

October 6, 2012
Boston University School of Medicine (BUSM) investigators have led the first genome-wide evaluation of genetic variants associated with Parkinson's disease (PD). The study, which is published online in PLOS ONE, points to ...

Prediction of susceptible genes associated with diabetes risk

April 20, 2016
The Institute for Infocomm Research (I²R) is a member of the Agency for Science, Technology and Research (A*STAR) family and is Singapore's largest ICT research institute. Established in 2002, our vision is to power a vibrant ...

Recommended for you

Researchers find inhibiting one protein destroys toxic clumps seen in Parkinson's disease

November 14, 2018
A defining feature of Parkinson's disease is the clumps of alpha-synuclein protein that accumulate in the brain's motor control area, destroying dopamine-producing neurons. Natural processes can't clear these clusters, known ...

Scalpel-free surgery enhances quality of life for Parkinson's patients, study finds

November 9, 2018
A high-tech form of brain surgery that replaces scalpels with sound waves improved quality of life for people with Parkinson's disease that has resisted other forms of treatment, a new study has found.

Singing may reduce stress, improve motor function for people with Parkinson's disease

November 7, 2018
Singing may provide benefits beyond improving respiratory and swallow control in people with Parkinson's disease, according to new data from Iowa State University researchers.

Scientists overturn odds to make Parkinson's discovery

November 7, 2018
Scientists at the University of Dundee have confirmed that a key cellular pathway that protects the brain from damage is disrupted in Parkinson's patients, raising the possibility of new treatments for the disease.

Road to cell death more clearly identified for Parkinson's disease

November 1, 2018
In experiments performed in mice, Johns Hopkins researchers report they have identified the cascade of cell death events leading to the physical and intellectual degeneration associated with Parkinson's disease.

Appendix removal is linked to lower risk of Parkinson's

October 31, 2018
Scientists have found a new clue that Parkinson's disease may get its start not in the brain but in the gut—maybe in the appendix.


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.