Variant in UBQLN4 gene is linked to ALS, study finds

Scientists at Northwestern University Feinberg School of Medicine have linked a novel variant in the UBQLN4 gene to amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron disease.

ALS, also known as Lou Gehrig's disease and motor neuron disease (MND), is a fatal disorder of motor neurons. The disease is characterized by progressive paralysis and death. Currently, no treatment substantially slows disease progression. The etiological underpinnings of ALS are complex and not fully understood. A lot of genes have been implicated in ALS, including C9orf72, SOD1, TARDBP, and FUS, which are key to the normal function of motor neurons and other cells.

Described in the journal eLife, the new study provides the first evidence that a variant in the UBQLN4 gene is linked with ALS. The study, led by Dr. Yongchao Ma from Northwestern University Feinberg School of Medicine, reveals that the UBQLN4 gene variant disrupts a pathway that drives motor neuron development.

Previous studies suggest that mutations in the UBQLN4 gene may trigger ALS and ALS/dementia in humans. In the current study, Dr. Ma and colleagues screened the UBQLN family of genes in patients with familial ALS and identified a novel variant in UBQLN4 that is associated with ALS. They further demonstrated that the UBQLN4 gene variant impairs a pathway involved in breaking down a protein called beta-catenin, leading to the buildup of the protein. This, in turn, impairs motor neuron structure.

When the researchers used a drug to inhibit beta-catenin function in a Zebrafish model, the defects in motor neurons caused by the UBQLN4 gene variant were reversed. The drug, called quercetin, is a flavonol found in many plants. Quercetin is used as an ingredient in supplements and has been promoted for the treatment of many human diseases including cancer.

Collectively, the findings indicate that inhibition of beta-catenin function may be a treatment strategy for patients with ALS who have the UBQLN4 variant. The findings, if confirmed, may lead to new therapies for this devastating degenerative disease.
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