ALS drugs
Medical Research

Study Opens A New Door for ALS Drug Discovery

For the first time, scientists at the University of North Carolina Health Care in Chapel Hill have pinned down the structure of toxic clumps of a protein associated with a large number of Amyotropic Lateral Sclerosis (ALS) cases, opening new avenues in the pursuit of drugs to stem the disease.

To create treatments for a disease which currently has none, scientists need to study and understand the driving forces behind the faulty biology. On December 28th 2015, the University of North Carolina School of Medicine researchers announced the first-ever evidence-based description of the neuronal protein clumps thought to be important in ALS, also known as Lou Gehrig’s disease, a fatal neurodegenerative condition.

The study, published online in Proceedings of the National Academy of Sciences, also provides the first definitive evidence that these protein clumps are indeed toxic to the type of neurons that die in patients with ALS.

This research development could be a crucial step toward developing drugs to stop the creation of the clumps and stem the progression of the disease. Cures for ALS and other neurodegenerative diseases have long eluded researchers, largely because their causes have remained mysterious.

A release from the university quotes senior study author Nikolay Dokholyan, PhD, the Michael Hooker Distinguished Professor of Biochemistry and Biophysics at UNC, as saying, “One of the biggest puzzles in health care is how to address neurodegenerative diseases; unlike many cancers and other conditions, we currently have no leverage against these neurodegenerative diseases. This study is a big breakthrough because it sheds light on the origin of motor neuron death and could be very important for drug discovery.”

Patients with ALS suffer gradual paralysis and early death as a result of the loss of motor neurons, which are crucial to moving, speaking, swallowing, and breathing.

The study focuses on a subset of ALS cases – an estimated 1 to 2 percent – that are associated with variations in a protein known as SOD1. However, even in patients without mutations in their SOD1 gene, this protein has been shown to form potentially toxic clumps. The researchers discovered that the protein forms temporary clumps of three, known as a “trimer,” and that these clumps are capable of killing motor neuron-like cells grown in the laboratory.

“This is a major step because nobody has known exactly what toxic interactions are behind the death of motor neurons in patients with ALS,” said Elizabeth Proctor, PhD, a graduate student in Dokholyan’s laboratory at the time of the study and the paper’s first author. “Knowing what these trimers look like, we can try to design drugs that would stop them from forming, or sequester them before they can do damage. We are very excited about the possibilities.”