TY - JOUR
T1 - TIA1 variant drives myodegeneration in multisystem proteinopathy with SQSTM1 mutations
AU - Lee, Youjin
AU - Jonson, Per Harald
AU - Sarparanta, Jaakko
AU - Palmio, Johanna
AU - Sarkar, Mohona
AU - Vihola, Anna
AU - Evilä, Anni
AU - Suominen, Tiina
AU - Penttilä, Sini
AU - Savarese, Marco
AU - Johari, Mridul
AU - Minot, Marie Christine
AU - Hilton-Jones, David
AU - Maddison, Paul
AU - Chinnery, Patrick
AU - Reimann, Jens
AU - Kornblum, Cornelia
AU - Kraya, Torsten
AU - Zierz, Stephan
AU - Sue, Carolyn
AU - Goebel, Hans
AU - Azfer, Asim
AU - Ralston, Stuart H.
AU - Hackman, Peter
AU - Bucelli, Robert C.
AU - Taylor, J. Paul
AU - Weihl, Conrad C.
AU - Udd, Bjarne
N1 - Funding Information:
CCW was supported by NIH (AG031867, AG042095, and AR068797); the Muscular Dystrophy Association; the Myositis Association; and the Hope Center for Neurological Disorders. BU was supported by the Academy of Finland; the Erkko Foundation; the Sigrid Juselius Foundation; the Folkhalsan Institute of Genetics; and Tampere University Hospital Medical Research Funds. JPT was supported by the NIH (R35NS097974); St. Jude and the American Lebanese Syrian Associated Charities (ALSAC); and the Howard Hughes Medical Institute. We thank Helena Luque (the Folkhalsan Institute of Genetics) for technical assistance.
Funding Information:
CCW was supported by NIH (AG031867, AG042095, and AR068797); the Muscular Dystrophy Association; the Myositis Association; and the Hope Center for Neurological Disorders. BU was supported by the Academy of Finland; the Erkko Foundation; the Sigrid Jusélius Foundation; the Folkhälsan Institute of Genet- ics; and Tampere University Hospital Medical Research Funds. JPT was supported by the NIH (R35NS097974); St. Jude and the American Lebanese Syrian Associated Charities (ALSAC); and the Howard Hughes Medical Institute. We thank Helena Luque (the Folkhälsan Institute of Genetics) for technical assistance.
Publisher Copyright:
© 2018 Blackwell Publishing Ltd. All rights reserved.
PY - 2018/3/1
Y1 - 2018/3/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85042741375&partnerID=8YFLogxK
U2 - 10.1172/JCI97103
DO - 10.1172/JCI97103
M3 - Article
C2 - 29457785
AN - SCOPUS:85042741375
VL - 128
SP - 1164
EP - 1177
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 3
ER -