Disrupted autophagy and neuronal dysfunction in C. elegans knockin models of FUS amyotrophic lateral sclerosis
Saba N. Baskoylu,
Natalie Chapkis,
Burak Unsal,
Jeremy Lins,
Kelsey Schuch,
Jonah Simon,
Anne C. Hart
Affiliations
Saba N. Baskoylu
Department of Neuroscience and the Robert J. & Nancy D. Carney Institute for Brain Sciences, Brown University, Providence, RI 02906, USA
Natalie Chapkis
Department of Neuroscience and the Robert J. & Nancy D. Carney Institute for Brain Sciences, Brown University, Providence, RI 02906, USA
Burak Unsal
Department of Neuroscience and the Robert J. & Nancy D. Carney Institute for Brain Sciences, Brown University, Providence, RI 02906, USA; Department of Molecular Biology and Genetics, Bogazici University, Istanbul 34342, Turkey
Jeremy Lins
Department of Neuroscience and the Robert J. & Nancy D. Carney Institute for Brain Sciences, Brown University, Providence, RI 02906, USA
Kelsey Schuch
Department of Molecular Biology, Cellular Biology & Biochemistry, Brown University, Providence, RI 02906, USA
Jonah Simon
Department of Neuroscience and the Robert J. & Nancy D. Carney Institute for Brain Sciences, Brown University, Providence, RI 02906, USA
Anne C. Hart
Department of Neuroscience and the Robert J. & Nancy D. Carney Institute for Brain Sciences, Brown University, Providence, RI 02906, USA; Corresponding author
Summary: How mutations in FUS lead to neuronal dysfunction in amyotrophic lateral sclerosis (ALS) patients remains unclear. To examine mechanisms underlying ALS FUS dysfunction, we generate C. elegans knockin models using CRISPR-Cas9-mediated genome editing, creating R524S and P525L ALS FUS models. Although FUS inclusions are not detected, ALS FUS animals show defective neuromuscular function and locomotion under stress. Unlike animals lacking the endogenous FUS ortholog, ALS FUS animals have impaired neuronal autophagy and increased SQST-1 accumulation in motor neurons. Loss of sqst-1, the C. elegans ortholog for ALS-linked, autophagy adaptor protein SQSTM1/p62, suppresses both neuromuscular and stress-induced locomotion defects in ALS FUS animals, but does not suppress neuronal autophagy defects. Therefore, autophagy dysfunction is upstream of, and not dependent on, SQSTM1 function in ALS FUS pathogenesis. Combined, our findings demonstrate that autophagy dysfunction likely contributes to protein homeostasis and neuromuscular defects in ALS FUS knockin animals.
