NIH Grant Supports Research Into FUS Mutations, Protein Toxicity

The National Institutes of Health (NIH) has awarded a $450,000 grant to a university research team to explore mutations in the FUS gene that contribute to amyotrophic lateral sclerosis (ALS), and to study genes showing a potential to counteract FUS protein toxicity.

The three-year project will be led by principal investigator Shulin Ju, PhD, and co-investigator Quan Zhong, PhD, both associate professors of biological sciences at Wright State University, in Ohio. 

“Understanding why FUS is toxic and how modifier genes enable cells to survive hopefully will lead to the discovery of novel therapeutic targets, which are desperately needed for curing this devastating disease,” Ju said in a university press release. 

Mutations in the FUS gene cause around 5% of familial ALS cases, and have also been linked to a small percentage of sporadic ALS cases. More than 80 distinct ALS-associated FUS mutations have been identified.

This gene provides the instructions for making the FUS protein, which is involved in transporting RNA molecules — blueprints of genes used to make proteins — from the cell’s nucleus to its cytoplasm. It is also involved in different steps of RNA and protein metabolism.

The FUS protein is mostly found in the nucleus, but in ALS patients it becomes misplaced in the cytoplasm where it forms toxic RNA granules.

As this cellular toxicity can be replicated in yeast cells, previous research from Ju and Zhong used yeast models to investigate whether increasing the levels of certain genes can suppress FUS-induced cell toxicity.

“Yeast has been commonly used in the scientific field as a model system to study fundamental cellular pathways that are conserved from yeast to human,” Ju said.

From a collection of 13,570 initial genes, a total of 37 genetic modifiers were identified. Most of these genes were also involved in the regulation of RNA, and competed with the mutated FUS protein to prevent the formation of toxic granules.

According to Ju, the funding will support additional research into these genes, to understand how they they interact with each other and prevent FUS-related toxicity.

“The next challenge is to figure out how these newly identified genes interact with FUS or with each other, and how their functions in regulating RNA granules may be required for rescuing cells from FUS-induced toxicity,” Ju said. 

Last year, Zhong received a research grant from NIH’s National Institute on Aging for a project using a similar genetic screening approach to identify genes that suppress alpha-synuclein, a protein whose toxic accumulation is a hallmark of Parkinson’s disease.