Researchers at the University of Maryland School of Medicine (UMSOM) have identified how certain gene mutations cause Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease. The pathway identified by the researchers may also be responsible for a certain form of dementia related to ALS.
The finding could offer potential new approaches for treating this devastating condition, which causes progressive, fatal paralysis and sometimes mental deterioration similar to Alzheimer’s disease. Their discovery was published this week in the Proceedings of the National Academy of Sciences (PNAS) and included collaborators from Harvard University, University of Auckland, King’s College London, and Northwestern University.
More than 5,000 Americans are diagnosed with ALS every year, a condition that is usually fatal and has no cure. Patients with ALS slowly lose the ability to move their muscles, leading to problems with basic functions such as breathing and swallowing. About half of ALS patients also develop dementia. Genetic studies of families with a predisposition to develop ALS have shown that the condition can be associated with certain gene mutations. Some of these mutations involve the gene UBQLN2 which regulates the disposal of misfolded “garbage” from the body’s cells. Until now, researchers did not fully understand how UBQLN2 mutations interfere with this pathway and cause ALS.
“We mapped out the process by which ubiquilin-2 (UBQLN2) gene mutations disrupt an important recycling pathway that cells use to get rid of their trash. Without this recycling, misfolded proteins build up in the nerve cell and become toxic, eventually destroying the cell. This destruction could lead to neurodegenerative disorders like ALS.” said Mervyn Monteiro, PhD, Professor of Anatomy and Neurobiology
To investigate how UBQLN2 mutations cause ALS, Dr. Monteiro’s group used both human cells and UBQLN2-mutant mouse models for their investigations. The mouse models, which they described in a 2016 PNAS publication, mimic the progression of the disease in people who inherit these gene mutations.
“Our new findings are exciting because similar acidification defects have been found in Alzheimer’s, Parkinson’s and Down syndrome,” Dr. Monteiro said. “This suggests that restoration of the defect could have broad implications for not only treating ALS, but possibly other neurodegenerative diseases as well.”
