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Mutant protein in muscle linked to neuromuscular disorder

Date:
April 16, 2014
Source:
University of California, San Diego Health Sciences
Summary:
Spinal and bulbar muscular atrophy (SBMA) is a rare inherited neuromuscular disorder characterized by slowly progressive muscle weakness and atrophy. In a new study, a team of scientists say novel mouse studies indicate that mutant protein levels in muscle cells are fundamentally involved in SBMA, suggesting an alternative and promising new avenue of treatment.

This is a graphic of the SBMA mouse model.
Credit: UC San Diego School of Medicine

Sometimes known as Kennedy's disease, spinal and bulbar muscular atrophy (SBMA) is a rare inherited neuromuscular disorder characterized by slowly progressive muscle weakness and atrophy. Researchers have long considered it to be essentially an affliction of primary motor neurons -- the cells in the spinal cord and brainstem that control muscle movement.

But in a new study published in the April 16, 2014 online issue of Neuron, a team of scientists at the University of California, San Diego School of Medicine say novel mouse studies indicate that mutant protein levels in muscle cells, not motor neurons, are fundamentally involved in SBMA, suggesting an alternative and promising new avenue of treatment for a condition that is currently incurable.

SBMA is an X-linked recessive disease that affects only males, though females carrying the defective gene have a 50:50 chance of passing it along to a son. It belongs to a group of diseases, such as Huntington's disease, in which a C-A-G DNA sequence is repeated too many times, resulting in a protein with too many glutamines (an amino acid), causing the diseased protein to misfold and produce harmful consequences for affected cells. Thus far, human clinical trials of treatments to protect against these repeat toxicities have failed.

In the new paper, a team led by principal investigator Albert La Spada, MD, PhD, professor of pediatrics, cellular and molecular medicine, and neurosciences, and the associate director of the Institute for Genomic Medicine at UC San Diego, propose a different therapeutic target. After creating a new mouse model of SBMA, they discovered that skeletal muscle was the site of mutant protein toxicity and that measures which mitigated the protein's influence in muscle suppressed symptoms of SBMA in treated mice, such as weight loss and progressive weakness, and increased survival.

In a related paper, published in the April 16, 2014 online issue of Cell Reports, La Spada and colleagues describe a potential treatment for SBMA. Currently, there is none.

The scientists developed antisense oligonucleotides -- sequences of synthesized genetic material -- that suppressed androgen receptor (AR) gene expression in peripheral tissues, but not in the central nervous system. Mutations in the AR gene are the cause of SBMA, a discovery that La Spada made more than 20 years ago while a MD-PhD student.

La Spada said that antisense therapy helped mice modeling SBMA to recover lost muscle weight and strength and extended survival.

"The main points of these papers is that we have identified both a genetic cure and a drug cure for SBMA -- at least in mice. The goal now is to further develop and refine these ideas so that we can ultimately test them in people," La Spada said.


Story Source:

The above story is based on materials provided by University of California, San Diego Health Sciences. Note: Materials may be edited for content and length.


Journal Reference:

  1. ConstanzaJ. Cortes, Shuo-Chien Ling, LingT. Guo, Gene Hung, Taiji Tsunemi, Linda Ly, Seiya Tokunaga, Edith Lopez, BryceL. Sopher, C.Frank Bennett, G.Diane Shelton, DonW. Cleveland, AlbertR. LaSpada. Muscle Expression of Mutant Androgen Receptor Accounts for Systemic and Motor Neuron Disease Phenotypes in Spinal and Bulbar Muscular Atrophy. Neuron, 2014; 82 (2): 295 DOI: 10.1016/j.neuron.2014.03.001

Cite This Page:

University of California, San Diego Health Sciences. "Mutant protein in muscle linked to neuromuscular disorder." ScienceDaily. ScienceDaily, 16 April 2014. <www.sciencedaily.com/releases/2014/04/140416162516.htm>.
University of California, San Diego Health Sciences. (2014, April 16). Mutant protein in muscle linked to neuromuscular disorder. ScienceDaily. Retrieved September 21, 2014 from www.sciencedaily.com/releases/2014/04/140416162516.htm
University of California, San Diego Health Sciences. "Mutant protein in muscle linked to neuromuscular disorder." ScienceDaily. www.sciencedaily.com/releases/2014/04/140416162516.htm (accessed September 21, 2014).

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