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, which could offer potential new approaches for treating this condition, was published recently in Proceedings of the National Academy of Sciences (PNAS) and included collaborators from Harvard University, University of Auckland, King’s College London, and Northwestern University.
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, a media release from University of Maryland School of Medicine explains.
“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,” says Mervyn Monteiro, PhD, Professor of Anatomy and Neurobiology, who is affiliated with the UMSOM’s Center for Biomedical Engineering and Technology (BioMET) at UMSOM.
“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.”
To investigate how UBQLN2 mutations cause ALS, 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.
Monteiro’s group first removed the UBQLN2 gene from human cells and found it completely stalled the recycling pathway. They then reintroduced either the normal gene or one of five gene mutations into the cells. They suggest that reintroduction of normal UBQLN2 restored the recycling pathway while all five of the gene mutations failed to restart the pathway.
Using the mouse model, Monteiro and his colleagues outlined the reason for the pathway disruption in the presence of gene mutations. They further suggest that the mice with the gene mutations had reduced levels of a certain protein called ATP6v1g1, which is an essential part of a pump that acidifies the cell’s trash container in order to initiate the breakdown and recycling process, the release continues.
“Our new findings are exciting because similar acidification defects have been found in Alzheimer’s, Parkinson’s and Down syndrome,” Monteiro comments. “This suggests that restoration of the defect could have broad implications for not only treating ALS, but possibly other neurodegenerative diseases as well.”
[Source(s): University of Maryland School of Medicine, EurekAlert]
