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TIA1 variant drives myodegeneration in multisystem proteinopathy with SQSTM1 mutations
YouJin Lee, … , Conrad C. Weihl, Bjarne Udd
YouJin Lee, … , Conrad C. Weihl, Bjarne Udd
Published February 19, 2018
Citation Information: J Clin Invest. 2018;128(3):1164-1177. https://doi.org/10.1172/JCI97103.
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Research Article Genetics Muscle biology

TIA1 variant drives myodegeneration in multisystem proteinopathy with SQSTM1 mutations

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Abstract

Multisystem proteinopathy (MSP) involves disturbances of stress granule (SG) dynamics and autophagic protein degradation that underlie the pathogenesis of a spectrum of degenerative diseases that affect muscle, brain, and bone. Specifically, identical mutations in the autophagic adaptor SQSTM1 can cause varied penetrance of 4 distinct phenotypes: amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Paget’s disease of the bone, and distal myopathy. It has been hypothesized that clinical pleiotropy relates to additional genetic determinants, but thus far, evidence has been lacking. Here, we provide evidence that a TIA1 (p.N357S) variant dictates a myodegenerative phenotype when inherited, along with a pathogenic SQSTM1 mutation. Experimentally, the TIA1-N357S variant significantly enhances liquid-liquid–phase separation in vitro and impairs SG dynamics in living cells. Depletion of SQSTM1 or the introduction of a mutant version of SQSTM1 similarly impairs SG dynamics. TIA1-N357S–persistent SGs have increased association with SQSTM1, accumulation of ubiquitin conjugates, and additional aggregated proteins. Synergistic expression of the TIA1-N357S variant and a SQSTM1-A390X mutation in myoblasts leads to impaired SG clearance and myotoxicity relative to control myoblasts. These findings demonstrate a pathogenic connection between SG homeostasis and ubiquitin-mediated autophagic degradation that drives the penetrance of an MSP phenotype.

Authors

YouJin Lee, Per Harald Jonson, Jaakko Sarparanta, Johanna Palmio, Mohona Sarkar, Anna Vihola, Anni Evilä, Tiina Suominen, Sini Penttilä, Marco Savarese, Mridul Johari, Marie-Christine Minot, David Hilton-Jones, Paul Maddison, Patrick Chinnery, Jens Reimann, Cornelia Kornblum, Torsten Kraya, Stephan Zierz, Carolyn Sue, Hans Goebel, Asim Azfer, Stuart H. Ralston, Peter Hackman, Robert C. Bucelli, J. Paul Taylor, Conrad C. Weihl, Bjarne Udd

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Figure 3

SQSTM1 is necessary for SG homeostasis.

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SQSTM1 is necessary for SG homeostasis.
(A) Immunofluorescence images of...
(A) Immunofluorescence images of control or SQSTM1-knockout MEFs (p62–/–) incubated at 42°C for 1 hour and returned to 37°C for the indicated durations followed by immunostaining for TIA1 (green) and G3BP1 (red) to detect SGs. (B) Graph of the percentage of cells containing TIA1/G3BP1-positive SGs as in A. Transfected cells were counted and are indicated as the total number of cells. Representative data were pooled from 3 independent experiments (n = 150~200). (C) Immunofluorescence images of MEFs expressing GFP-TIA1-WT, -NS, or -EK and immunostained with SQSTM1 antibody following incubation at 42°C for 1 hour and reincubation at 37°C for the indicated durations. (D) Bar graph of the percentage of GFP-TIA1/SQSTM1-positive SGs in C. Individual GFP-TIA1 SGs were counted and are indicated as the total number of SGs. Representative data were pooled from 3 independent experiments (n = 800~1000). Scale bars: 5 μm. Error bars represent the mean ± SEM. (B and D) *P < 0.05 by 2-way ANOVA and 2-tailed Student’s t test.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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