Abstract
Mutations in fused in sarcoma (FUS) lead to amyotrophic lateral sclerosis (ALS) with varying ages of onset, progression and severity. This suggests that unknown genetic factors contribute to disease pathogenesis. Here we show the identification of muscleblind as a novel modifier of FUS-mediated neurodegeneration in vivo. Muscleblind regulates cytoplasmic mislocalization of mutant FUS and subsequent accumulation in stress granules, dendritic morphology and toxicity in mammalian neuronal and human iPSC-derived neurons. Interestingly, genetic modulation of endogenous muscleblind was sufficient to restore survival motor neuron (SMN) protein localization in neurons expressing pathogenic mutations in FUS, suggesting a potential mode of suppression of FUS toxicity. Upregulation of SMN suppressed FUS toxicity in Drosophila and primary cortical neurons, indicating a link between FUS and SMN. Our data provide in vivo evidence that muscleblind is a dominant modifier of FUS-mediated neurodegeneration by regulating FUS-mediated ALS pathogenesis.
Highlights
Mutations in fused in sarcoma (FUS) lead to amyotrophic lateral sclerosis (ALS) with varying ages of onset, progression and severity
To further validate whether Mbl is a novel modifier of FUS-induced toxicity in vivo, in addition to the loss of function approach, we undertook a gain of function approach by generating flies that overexpress fly Mbl that showed an enhancement in the FUS toxicity
The effect on the number of intersections was dampened by co-transfecting the neurons with Mbnl[1] short-hairpin RNAs (shRNA). These results suggest that muscleblind-like protein 1 (MBNL1) regulates the pathological and morphological defects associated with FUS expression in mammalian models by controlling FUS distribution and interaction with stress granules
Summary
Mutations in fused in sarcoma (FUS) lead to amyotrophic lateral sclerosis (ALS) with varying ages of onset, progression and severity This suggests that unknown genetic factors contribute to disease pathogenesis. Pathogenic mutations of FUS were first identified in ALS patients in 2009 and were found to cause mislocalization of the disease protein from the nucleus to the cytoplasm and accumulation into cytoplasmic aggregates, commonly regarded to as stress granules (SGs)[25,26]. ALS is a heterogeneous disease condition where the age of onset and disease progression varies significantly between individuals who share a single-point mutation in an ALS-causing gene[54] This is true for both sALS patients and fALS cases where all affected family members have the same point mutation[55].
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