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; Udai Bhan Pandey

doi:10.1038/s41467-019-13383-z

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, Udai Bhan Pandey^*

^*Corresponding author for this work

Basic and Clinical Neuroscience

Research output: Contribution to journal › Article › peer-review

23 Citations (Scopus)

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.

Original language	English
Article number	5583
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-13383-z
Publication status	Published - 1 Dec 2019

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Casci, I., Krishnamurthy, K., Kour, S., Tripathy, V., Ramesh, N., Anderson, E. N., Marrone, L., Grant, R. A., Oliver, S., Gochenaur, L., Patel, K., Sterneckert, J., Gleixner, A. M., Donnelly, C. J., Ruepp, M. D., Sini, A. M., Zuccaro, E., Pennuto, M., Pasinelli, P., & Bhan Pandey, U. (2019). Muscleblind acts as a modifier of FUS toxicity by modulating stress granule dynamics and SMN localization. Nature Communications, 10(1), Article 5583. https://doi.org/10.1038/s41467-019-13383-z

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

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.",

author = "Ian Casci and Karthik Krishnamurthy and Sukhleen Kour and Vadreenath Tripathy and Nandini Ramesh and Anderson, {Eric N.} and Lara Marrone and Grant, {Rogan A.} and Stacie Oliver and Lauren Gochenaur and Krishani Patel and Jared Sterneckert and Gleixner, {Amanda M.} and Donnelly, {Christopher J.} and Ruepp, {Marc David} and Sini, {Antonella M.} and Emanuela Zuccaro and Maria Pennuto and Piera Pasinelli and {Bhan Pandey}, Udai",

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doi = "10.1038/s41467-019-13383-z",

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Casci, I, Krishnamurthy, K, Kour, S, Tripathy, V, Ramesh, N, Anderson, EN, Marrone, L, Grant, RA, Oliver, S, Gochenaur, L, Patel, K, Sterneckert, J, Gleixner, AM, Donnelly, CJ, Ruepp, MD, Sini, AM, Zuccaro, E, Pennuto, M, Pasinelli, P & Bhan Pandey, U 2019, 'Muscleblind acts as a modifier of FUS toxicity by modulating stress granule dynamics and SMN localization', Nature Communications, vol. 10, no. 1, 5583. https://doi.org/10.1038/s41467-019-13383-z

TY - JOUR

T1 - Muscleblind acts as a modifier of FUS toxicity by modulating stress granule dynamics and SMN localization

AU - Casci, Ian

AU - Krishnamurthy, Karthik

AU - Kour, Sukhleen

AU - Tripathy, Vadreenath

AU - Ramesh, Nandini

AU - Anderson, Eric N.

AU - Marrone, Lara

AU - Grant, Rogan A.

AU - Oliver, Stacie

AU - Gochenaur, Lauren

AU - Patel, Krishani

AU - Sterneckert, Jared

AU - Gleixner, Amanda M.

AU - Donnelly, Christopher J.

AU - Ruepp, Marc David

AU - Sini, Antonella M.

AU - Zuccaro, Emanuela

AU - Pennuto, Maria

AU - Pasinelli, Piera

AU - Bhan Pandey, Udai

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

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DO - 10.1038/s41467-019-13383-z

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AN - SCOPUS:85076314840

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5583

ER -

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

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