Muscleblind acts as a modifier of FUS toxicity by modulating stress granule dynamics and SMN localization

Ian Casci, Karthik Krishnamurthy, Sukhleen Kour, Vadreenath Tripathy, Nandini Ramesh, Eric N. Anderson, Lara Marrone, Rogan A. Grant, Stacie Oliver, Lauren Gochenaur, Krishani Patel, Jared Sterneckert, Amanda M. Gleixner, Christopher J. Donnelly, Marc-David Ruepp, Antonella M. Sini, Emanuela Zuccaro, Maria Pennuto, Piera Pasinelli and Udai Bhan Pandey ()
Additional contact information
Ian Casci: University of Pittsburgh Graduate School of Public Health
Karthik Krishnamurthy: Jefferson University
Sukhleen Kour: University of Pittsburgh Medical Center
Vadreenath Tripathy: Technische Universität Dresden, Fetscherstr. 105
Nandini Ramesh: University of Pittsburgh Graduate School of Public Health
Eric N. Anderson: University of Pittsburgh Medical Center
Lara Marrone: Technische Universität Dresden, Fetscherstr. 105
Rogan A. Grant: University of Pittsburgh Medical Center
Stacie Oliver: University of Pittsburgh Medical Center
Lauren Gochenaur: University of Pittsburgh Medical Center
Krishani Patel: University of Pittsburgh Medical Center
Jared Sterneckert: Technische Universität Dresden, Fetscherstr. 105
Amanda M. Gleixner: University of Pittsburgh
Christopher J. Donnelly: University of Pittsburgh
Marc-David Ruepp: UK Dementia Research Institute at King’s College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King’s College London
Antonella M. Sini: University of Padova
Emanuela Zuccaro: University of Padova
Maria Pennuto: University of Padova
Piera Pasinelli: Jefferson University
Udai Bhan Pandey: University of Pittsburgh Graduate School of Public Health

Nature Communications, 2019, vol. 10, issue 1, 1-20

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13383-z

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