Identification of protein interactions that regulate FUS mislocalization and aggregation in ALS

Mutations in a gene called FUS can lead to potentially toxic, abnormal aggregation (or clumping) of the FUS protein within motor neurons. These mutations are strongly linked to the development of ALS. The exact mechanisms, however, for how this complex aggregation occurs and how this impacts key functions within motor neurons remain poorly understood.

Normally, the FUS protein is found primarily in the nucleus, the central part of the cell where our DNA is stored. When FUS mutations are present, these proteins leak out from the nucleus and accumulate in the cytoplasm. Dr. Youn and her team hypothesize that this change in location of the FUS protein results in different protein interactions within the cell that influence its toxic aggregation, and ultimately motor neuron health.

In this study, the researchers will use a technique called BioID to verify which protein interactions are gained or lost when FUS is transported outside of the nucleus, and additionally, how age-related stress impacts these. This work will help us to better understand how FUS mutations or age-related stress drive ALS and help to identify novel treatment strategies. This work also provides a model to test the cellular interactions of other ALS-linked proteins, which will be an invaluable tool to learn more about the molecular pathways that contribute to disease.