Featured Research

from universities, journals, and other organizations

Possible cause of, and treatment for, non-familial Parkinson's

Date:
February 6, 2013
Source:
Columbia University Medical Center
Summary:
Researchers have identified a protein trafficking defect within brain cells that may underlie the common form of Parkinson's disease. The defect is at a point of convergence for the action of at least three different genes that had been implicated in prior studies of Parkinson's disease. Whereas most molecular studies focus on mutations associated with rare familial forms of the disease, these findings relate directly to the common non-familial form of Parkinson’s.

Researchers have identified a protein trafficking defect within brain cells that may underlie the common form of Parkinson's disease.
Credit: © Nenov Brothers / Fotolia

Columbia University Medical Center (CUMC) researchers have identified a protein trafficking defect within brain cells that may underlie common non-familial forms of Parkinson's disease. The defect is at a point of convergence for the action of at least three different genes that had been implicated in prior studies of Parkinson's disease. Whereas most molecular studies focus on mutations associated with rare familial forms of the disease, these findings relate directly to the common non-familial form of Parkinson's.

Related Articles


The study was published today in the online edition of the journal Neuron.

The defective pathway is called the "retromer" pathway, in part because it can guide the reutilization of key molecules by moving them back from the cell surface to internal stores. In this study, defects in the retromer pathway also appear to have profound effects on the cell's disposal machinery, which may explain why Parkinson's disease brain cells ultimately accumulate large protein aggregates. The trafficking defects associated with Parkinson's can be reversed by increasing retromer pathway activity, suggesting a possible therapeutic strategy. No current therapies for Parkinson's alter the progression of the disease.

The researchers also found evidence that, even in unaffected individuals who simply carry common genetic variants associated with an increased risk of Parkinson's disease, these molecular changes are at work. This supports the notion that early treatment approaches will be important in tackling Parkinson's disease.

"Taken together, the findings suggest that drugs that target the retromer pathway could help prevent or treat Parkinson's," said study leader Asa Abeliovich, MD, PhD, associate professor of pathology and cell biology and of neurology in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at CUMC.

In recent years, through genome-wide association studies (GWAS), researchers have identified about 10 common genetic variants that appear to have small effects on the risk of non-familial Parkinson's, However, it has been hard to delve deeper into the impact of these variants. "When you look at patient brain tissue at autopsy, it's usually too late -- all the critical dopamine neurons are long gone and the damage has been done," said Dr. Abeliovich.

In the current study, Dr. Abeliovich and his CUMC colleagues used an unusually broad array of approaches -- including analyses of Parkinson's disease-associated genetic variations, patient brain tissue, in vitro tissue culture studies of brain neurons, and fruit fly (Drosophila) models that harbor genetic variants related to those associated with Parkinson's disease.

The researchers found that common variants in two genes previously linked to Parkinson's disease, LRRK2 and RAB7L1, led to an unexpectedly similar impact on human brain tissue. The effects of the variants were found to be highly overlapping, pointing to a common pathway of action. Prominent cellular changes were observed in the retromer pathway, which is involved in the trafficking of proteins from the Golgi apparatus (which packages proteins for delivery to other cell components) to the lysosomes (which recycle proteins and other molecules). Mutations that affect the retromer pathway have also been found in familial Parkinson's disease. Earlier studies from Columbia's Taub Institute have shown that genetic variants in genes associated with retromer function are linked to Alzheimer's disease and retromer component levels appear altered in Alzheimer's disease brains, suggesting a broader role for retromer dysfunction in neurodegenerative diseases of aging, according to Dr. Abeliovich.

The impact of the RAB7L1 and LRRK2 variants was apparent even in individuals with no signs or symptoms of Parkinson's disease. This suggests that there is a pre-disease state in unaffected carriers of the two genetic variants that favors early disease onset and that, in theory, could be targeted therapeutically.

The CUMC researchers also demonstrated that overexpression of one of the variants, RAB7L1, can overcome the effects of the other variant. Similarly, expression of VPS35, a gene involved in the retromer pathway, can suppress LRRK2 mutant pathology. "It will be interesting to look for drugs that directly target these retromer components or that more generally promote flow through the pathway," said Dr. Abeliovich.

The title of the paper is "RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson's disease risk." The other contributors are David A. Macleod, Herve Rhinn, Tomoki Kuwahara, Ari Zolin, Gilbert Di Paolo, Brian D. McCabe, Lorraine N. Clark, and Scott A. Small, all at CUMC.

The study was supported by grants from the Michael J. Fox Foundation and the National Institutes of Health (NS064433, NS060876, NS060113, A6008702, AG025161, and AG08702-21.


Story Source:

The above story is based on materials provided by Columbia University Medical Center. Note: Materials may be edited for content and length.


Journal Reference:

  1. David A. MacLeod, Herve Rhinn, Tomoki Kuwahara, Ari Zolin, Gilbert Di Paolo, Brian D. MacCabe, Karen S. Marder, Lawrence S. Honig, Lorraine N. Clark, Scott A. Small, Asa Abeliovich. RAB7L1 Interacts with LRRK2 to Modify Intraneuronal Protein Sorting and Parkinson’s Disease Risk. Neuron, 2013; 77 (3): 425 DOI: 10.1016/j.neuron.2012.11.033

Cite This Page:

Columbia University Medical Center. "Possible cause of, and treatment for, non-familial Parkinson's." ScienceDaily. ScienceDaily, 6 February 2013. <www.sciencedaily.com/releases/2013/02/130206130946.htm>.
Columbia University Medical Center. (2013, February 6). Possible cause of, and treatment for, non-familial Parkinson's. ScienceDaily. Retrieved November 24, 2014 from www.sciencedaily.com/releases/2013/02/130206130946.htm
Columbia University Medical Center. "Possible cause of, and treatment for, non-familial Parkinson's." ScienceDaily. www.sciencedaily.com/releases/2013/02/130206130946.htm (accessed November 24, 2014).

Share This


More From ScienceDaily



More Health & Medicine News

Monday, November 24, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Are Female Bosses More Likely To Be Depressed?

Are Female Bosses More Likely To Be Depressed?

Newsy (Nov. 24, 2014) — A new study links greater authority with increased depressive symptoms among women in the workplace. Video provided by Newsy
Powered by NewsLook.com
Winter Can Cause Depression — Here's How To Combat It

Winter Can Cause Depression — Here's How To Combat It

Newsy (Nov. 23, 2014) — Millions of American suffer from seasonal depression every year. It can lead to adverse health effects, but there are ways to ease symptoms. Video provided by Newsy
Powered by NewsLook.com
Ebola-Hit Sierra Leone's Late Cocoa Leaves Bitter Taste

Ebola-Hit Sierra Leone's Late Cocoa Leaves Bitter Taste

AFP (Nov. 23, 2014) — The arable district of Kenema in Sierra Leone -- at the centre of the Ebola outbreak in May -- has been under quarantine for three months as the cocoa harvest comes in. Duration: 01:32 Video provided by AFP
Powered by NewsLook.com
Don't Fall For Flu Shot Myths

Don't Fall For Flu Shot Myths

Newsy (Nov. 23, 2014) — Misconceptions abound when it comes to your annual flu shot. Medical experts say most people older than 6 months should get the shot. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:

Strange & Offbeat Stories

 

Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins