Navigation Links
Loss of key protein boosts neuron loss in ALS
Date:3/4/2011

Amyotrophic lateral sclerosis, known as ALS or more popularly, Lou Gehrig's disease, is a notorious neurodegenerative condition characterized by the progressive deterioration of brain and spinal cord neurons, resulting in the gradual but catastrophic loss of muscle control and ultimately, death.

In a new paper, published in the Feb. 27 advance online edition of the journal Nature Neuroscience, a team of scientists at the University of California, San Diego School of Medicine and colleagues describe the profound and pervasive role of a key protein in ALS pathology called TDP-43.

The work was led by Don W. Cleveland, PhD, professor and chair of the UCSD Department of Cellular and Molecular Medicine and head of the Laboratory of Cell Biology at the Ludwig Institute for Cancer Research and Gene Yeo, PhD, assistant professor in the Department of Cellular and Molecular Medicine.

In normal cells, TDP-43 is found in the nucleus where it helps maintain proper levels of ribonucleic acid (RNA), intermediate molecules that translate genetic information from DNA to proteins the building blocks of cells.

In the majority of ALS patients, however, TDP-43 accumulates in the cell's cytoplasm the liquid that separates the nucleus from the outer membrane, and thus is excluded from the nucleus, which prevents it from performing its normal duties.

Using a mouse model, the researchers made three new important findings:

First, employing a comprehensive genome-wide RNA-binding mapping strategy, they discovered that more than one-third of the genes in the mouse brain are direct targets of TDP-43. In other words, the roles and functions of these genes are impacted by the presence or absence of normal TDP-43.

Second, the genes most affected had numerous TDP-43 binding sites on very long introns. Introns are the non-coding portions of a gene that are not used to make proteins. Typically, introns are removed (spliced out) during the development of mature messenger RNA. Introns, however, contain binding sites for RNA binding proteins such as TDP-43, to regulate the splicing process.

"This is an important finding as genes expressed in the central nervous system have much longer introns than genes expressed in any other tissues," said Yeo. "This may explain the neuronal selectivity of the disease, and why other types of cells aren't affected."

Third, TDP-43 affects the alternative splicing of many genes. In fact, it affects the alternative splicing of its own RNA message. Said Yeo: "This autoregulation keeps TDP-43 protein levels in check. The loss of TDP-43 removes this check; more TDP-43 is generated and more is likely to accumulate in the cytoplasm."

The deep and expansive impact of misaggregated TDP-43 and the concurrent loss of normal TDP-43 appear to extend beyond ALS. The protein is a central component in the pathogenesis of an ever-increasing list of neurodegenerative conditions. For example, accumulating abnormal TDP-43 in neuronal cytoplasm has been documented in frontotemporal lobar dementia, a neurological disorder that results in progressive changes in personality, the ability to concentrate, social skills, motivation and reasoning.

"It is likely that TDP-43 affects many other neurodegenerative diseases," said Yeo. "Our RNA targets probably reveal the set of genes important for maintaining the normal homeostasis of neurons."

Yeo said the team will now explore which TDP-43 binding sites are critical to how ALS begins and progresses. Ultimately, he said, the information could be used to design new drugs and therapies.


'/>"/>

Contact: Scott LaFee
slafee@ucsd.edu
619-543-6163
University of California - San Diego
Source:Eurekalert

Related medicine news :

1. Penn researchers find new role for cancer protein p53
2. Protein and microRNA block cellular transition vital to metastasis
3. Protein fuels inflammation in pancreatic and breast tumors
4. Scientists bioengineer a protein to fight leukemia
5. Higher Levels of Blood Protein Linked to Lower Respiratory Risks
6. Overabundance of protein expands breast cancer stem cells
7. Scientists develop method to identify fleetingly ordered protein structures
8. Protein may be key to new treatment in a childhood cancer
9. Scripps Research scientists develop powerful new methodology for stabilizing proteins
10. Key Protein May Warn of Future Spread of Cancer
11. Communication pathways within proteins may yield new drug targets to stop superbugs
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:10/13/2017)... Ill. (PRWEB) , ... October ... ... Edwardsville School of Pharmacy (SOP) alumni Hannah Randall, PharmD ‘17, and Jennifer ... healthcare professionals on guideline updates for the primary prevention of cardiovascular diseases ...
(Date:10/13/2017)... ... , ... Apple Rehab Shelton Lakes , which specializes in the delivery ... as part of a disaster drill on October 3rd. , Apple Rehab participated with ... Manager, as well as the Connecticut Long Term Care Mutual Aid Plan (LTC-MAP). ...
(Date:10/13/2017)... (PRWEB) , ... October 13, 2017 , ... The Visiting ... Day Market. Featuring a collection of specialty vendors and unique items from across the ... and quality-focused health and wellness services offered by the VNA. The boutique will ...
(Date:10/13/2017)... ... ... Global Healthcare Management’s 4th Annual Kids Fun Run brought out many kids this ... by Global Healthcare Management’s CEO, Jon Letko, is aimed at getting kids excited about ... ages; it is a non-competitive, non-timed event, which is all about having fun and ...
(Date:10/13/2017)... ... October 13, 2017 , ... ... giving viewers the lowdown on sciatica in a new episode of "Success Files," ... on current events and innovation and investigates each subject in-depth with passion and ...
Breaking Medicine News(10 mins):
(Date:10/10/2017)... Pa. , Oct. 10, 2017   West ... in innovative solutions for injectable drug administration, today shared ... West,s ID Adapter for improving the intradermal administration of ... Fourth Skin Vaccination Summit in May 2017 by Dr. ... Lead, Polio Department, World Health Organization (WHO), and recently ...
(Date:10/4/2017)... LAWRENCE, Mass. , Oct. 4, 2017 /PRNewswire/ ... developer of single-use, self-contained, illuminating medical devices, today ... National Health Surveillance Agency (or Agência Nacional ... ®. The first single-use, cordless surgical retractor with ... ONETRAC provides optimal access, illumination and exposure of ...
(Date:10/2/2017)... , Oct. 2, 2017 The Rebound mobile app ... struggle to reverse the tide of prescription drug addiction. The ... their medicine intake and stepping down their dosage in a ... launch in December 2017; the first 100,000 people to sign ... at http://www.rebound-solution.com/ ...
Breaking Medicine Technology: