Posts Tagged ‘National Institute of Neurological Disorders and Stroke’

ALS Breakthrough Research Could Lead to a Cure

Wednesday, August 31st, 2011

Researchers appear to have discovered the cause of amyotrophic lateral sclerosis (ALS),  commonly known as Lou Gehrig’s disease.  The discovery has the potential to lead to an effective treatment to the progressive, fatal disease.  According to Dr. Teepu Siddique, a neuroscientist at Northwestern University’s Feinberg School of Medicine, the key was discovering an underlying disease process for all types of ALS.  The breakthrough also could play a role in creating effective treatments for other neurodegenerative diseases such as Alzheimer’s, dementia and Parkinson’s, Siddique said.  The Northwestern research team said that the breakdown of cellular recycling systems in the neurons of the spinal cord and brain of ALS patients results in the nervous system gradually losing its ability to carry brain signals to the body’s muscular system.  When these signals are absent, patients are increasingly unable to move, talk, swallow or breathe. 

“This is the first time we could connect (ALS) to a clear-cut biomedical mechanism,” Siddique said. “It has really made the direction we have to take very clear and sharp.  We can now test for drugs that would regulate this protein pathway or optimize it, so it functions as it should in a normal state.”  The breakthrough was announced in the research journal Nature.  Approximately 30,000 Americans have ALS – a total of 350,000 patients across the globe.  With no known treatment, half of all ALS patients die within three years.  New York Yankee baseball star Lou Gehrig died in 1941 at the age of 37 of the disease that today bears his name. 

Mutations in a single gene known as UBQLN2  cause inherited forms of ALS and ALS with dementia, probably through defective degradation of abnormal protein clumps.  Even patients who did not have the UBQLN2 mutation had features of the disrupted pathway, suggesting that it is a “common pathological feature in a wide spectrum of ALS and ALS/dementia,” according to Dr. Siddique.  “These data provide robust evidence for an impairment of protein turnover in the pathogenesis of ALS and ALS/dementia, and possibly other neurodegenerative disorders, as well.  These pathways should provide novel molecular targets for the design of rational therapies for these disorders.” 

“The exact function of ubiquilin 2 is not well understood,” Siddique said.  “However, there is increasing evidence that ubiquilins, together with their interactions with other proteins, may be involved in neurodegenerative disorders.”  Siddique and his research team looked for other UBQLN2 mutations in 188 members of families with a history of ALS or ALS with dementia.  This work led to the identification of four additional mutations, none of which was present in a mutation database or in 928 control samples.

 Only 10 percent of ALS patients have the inherited form of the disease.  Because no cause had been identified for those who lack a family history, researchers have been uncertain about whether different forms of ALS were actually the same disease.  Siddique and his research team found that in people with and without inherited ALS, the disease results from the inability of a protein system to repair the nerve cells that tell the muscles what to do.  For ALS patients, ubiquilin2 does not do this effectively, leading to an accumulation of the damaged proteins and ubiquilin2 in vital nerve cells in the spinal cord and brain.  As seen through a microscope, the protein accumulations look like twisted balls of yarn, a hallmark of ALS.  “Abnormality in protein degradation has been suspected, but there was little direct evidence before this study,” said study co-author Han-Xiang Deng, M.D.  “This moves the field forward in an impressive way, but like many breakthroughs, many questions remain to be answered.”

Amelie Gubitz,  a research program director at the National Institute of Neurological Disorders and Stroke, said the study marks an important step forward.  “You need to understand at the cellular level what is going wrong,” Gubitz said.  “Then you can begin to design drugs.” 

Siddique, who has spent more than 25 years researching the causes and underlying mechanisms of ALS, said he was fascinated by the subject because “It was one of the most difficult problems in neurology and the most devastating, a disease without any treatment or known cause.  These people in the prime of their lives and the peak of their productivity get this devastating illness that kills them.  The people who get ALS/dementia, an even more vicious disease, have a double whammy.”