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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 1

Digenic inheritance of SQSTM1 and TIA1 variants leads to distal myopathy with RV-IBM pathology.

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Digenic inheritance of SQSTM1 and TIA1 variants leads to distal myopathy...
(A) Linear diagram of the TIA1 protein highlighting conserved regions of the LCD. Distal myopathy–associated variant positions are shown in yellow and ALS and FTD variants in blue. (B) Pedigrees of families IV, VII, and IX showing segregation. DNA was only available for the patients indicated with an asterisk. (C) Muscle imaging findings for patient V-2 at age 54 years. Severe involvement of all calf muscles was seen on MRI T1-weighted images. The solid white arrow indicates normal muscle, and the arrowhead indicates atrophic muscle with fatty replacement. (D) H&E staining of a muscle biopsy of the right tibialis from patient XII-1 showing several fibers with RVs (arrows). Original magnification, 50 μm. (E) Immunofluorescence staining of TIA1 (red) with SQSTM1 (green in upper panel) or TDP-43 (green in lower panel) revealed accumulation and partial colocalization of these proteins in the muscle biopsy from patient V-2. Both sets of images show a RV fiber. The dotted lines denote affected fiber. Scale bars: 50 μm.
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