Columbia scientists have provided new insights into how mutations in a gene called TBK cause amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disability that robs persons of movement, speech and ultimately, their lives.
The researchers found that ALS-associated mutations in TBK1 can have both positive and negative effects on the progression of disease in mice genetically modified to have ALS-like symptoms.
These findings, reported today in Neuron, provide both genetic and mechanistic insights that could lead to novel strategies for the development of treatments for ALS.
“One of the greatest challenges to finding a cure for ALS is using genetic data to understand the disease’s underlying mechanisms,” said Tom Maniatis, PhD, a principal investigator at Columbia’s Mortimer B. Zuckerman Mind Brain Behavior Institute. “For example, neurodegenerative disability such as ALS involve multiple cell types that are constantly changing as the disease progresses, so a drug that is beneficial in the early stages of the disease could be detrimental at later times. Our study provides a glimpse into the complex relationship between ALS genetics and its mechanisms, and highlights the challenge in developing safe and effective drugs to treat the disease,” commented Dr. Maniatis, the Isidore S. Edelman Professor of Biochemistry at Columbia’s Vagelos College of Physicians and Surgeons.
ALS is a disability of the spinal cord, which can be triggered by the accumulation of misfolded proteins in motor neurons, the nerve cells in the spinal cord that drive movement.
“Our study provides an example of how multiple pathways within and between cells can be targeted through manipulation of a single gene, and how modifying these pathways in ALS can be beneficial — or detrimental — at different stages of disease progression,” Dr. Gerbino added.
