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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.
Introduction
Pathogenic mutations in some genes lead to a spectrum of variably penetrant phenotypes that span different organs and postmitotic tissue (1-4). For example, the same mutation in the autophagic adaptor protein SQSTM1 (also known as p62) can cause Paget's disease of the bone (PDB), rimmed vacuolar inclusion body myopathy (RV-IBM), amyotrophic lateral sclerosis (ALS), or frontotemporal dementia (FTD) (1). The term multisystem proteinopathy (MSP) has become useful to describe this growing family of genetic diseases that so far have been reported to have dominant mutations in the pleotropic genes VCP, HNRNPA2B1, HNRNPA1,and SQSTM1 (1-4). Other disease-associated genes with variably penetrant phenotypic expression of RV-IBM, ALS, and FTD, yet no association with PDB, include TIA1 and MATR3 (5-7). One distinctive feature of the MSP pedigrees is that patients with the same mutation, and even the same mutation within a family, can manifest different phenotypes (i.e., PDB in 1 sibling and ALS in another sibling). MSP also unifies 2 key pathologic features in affected tissue: ubiquitinated aggregates and the accumulation of RNA-binding proteins with low-complexity sequence domains (LCDs) such as TDP-43 (4).
Mutations...