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Abstract
Multisystem proteinopathy (MSP) is a degenerative disorder combining amyotrophic lateral sclerosis, frontotemporal dementia, inclusion body myopathy and Paget’s disease of bone. Many MSP genes including Matrin3 (MATR3) encode RNA binding proteins, highlighting the role of RNA metabolism in MSP. Over a dozen mutations in MATR3 have been identified, but the mechanisms of MATR3 pathogenesis remain unknown.
To investigate MATR3-associated MSP, we developed a Drosophila model expressing wildtype or mutant MATR3 in indirect flight muscles, which exhibits an abnormal wing position and muscle degeneration. We simultaneously developed human neuronal cell lines stably expressing MATR3. In both fly and human cell models, wildtype and mutant MATR3 are localized in the nucleus. However, MATR3 S85C and F115C are less soluble than wildtype MATR3. A candidate genetic screen identified enhancers of mutant MATR3 toxicity and implicated cytoskeletal dysfunction in MATR3 pathogenesis. Together, this work may shed light on the mechanisms underlying MATR3-associated MSP.
