TIA1 variant drives myodegeneration in multisystem proteinopathy with SQSTM1 mutations

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.

Muscle pathology of hereditary motor and sensory neuropathy with proximal dominant involvement with TFG mutation

“…TDP‐43 is known to impair UPS activity by unknown mechanisms, while p62 serves as an adapter protein for selective autophagy that degrades ubiquitinated misfolded proteins by a lysosome system . Of note, the sarcoplasmic aggregates including TDP‐43 and p62 are a histological hallmark of inclusion body myopathy caused by the mutations of valosin‐containing protein (VCP) , hnRNPA2B1 , hnRNPA1 , matrin 3 , and TIA1/SQSTM1 genes . More interestingly, these mutations have been shown to cause multisystem proteinopathy (MSP), such as frontotemporal dementia, inclusion body myopathy, motor neuron disease, peripheral neuropathy, and Paget's disease of bone .…”

“…13 Of note, the sarcoplasmic aggregates including TDP-43 and p62 are a histological hallmark of inclusion body myopathy caused by the mutations of valosin-containing protein (VCP), hnRNPA2B1, hnRNPA1, matrin 3, and TIA1/SQSTM1 genes. [14][15][16][17][18] More interestingly, these mutations have been shown to cause multisystem proteinopathy (MSP), such as frontotemporal dementia, inclusion body myopathy, motor neuron disease, peripheral neuropathy, and…”

High diagnostic yield and novel variants in very late-onset spasticity

“…The very poor genotype-phenotype correlation may be due to the interaction of additional genetic factors that may explain the observation of patients with HSP7 phenotypes associated with single heterozygous mutations S anchez-Ferrero et al, 2013). There is precedent for the interaction of different Mendelian disease genes causing unique phenotypes (Balci et al, 2017;Posey et al, 2017), and detailed study of such situations can produce novel mechanistic insights (Lee et al, 2018;Niu et al, 2018). Given the extensive unexplained heterogeneity in HSP, particularly in SPG7-and SPAST-related disease, these conditions would appear to be the best candidates for study, to identify novel modifier mechanisms.…”

Natural and Pathogenic Protein Sequence Variation Affecting Prion-Like Domains Within and Across Human Proteomes

“…Importantly, the estimated PAPA score range for a number of proteins exceeds 0.2, indicating that sequence variation can have a dramatic effect on predicted aggregation propensity (by comparison, the PAPA score range=0.92 for the entire human proteome). Additionally, we examined the aggregation propensity ranges of prototypical prionlike proteins associated with human disease (21)(22)(23)(24)(25)(27)(28)(29)(30)(31)(32)(33)(34), which are identified as highscoring candidates by both PAPA and PLAAC. In most cases, the lowest aggregation propensity estimate derived from sequence variant sampling scored well-below the classical aggregation threshold (PAPA score=0.05), and the highest aggregation propensity estimate scored well-above the aggregation threshold ( Fig 1D).…”

“…identification of PrLD candidates with the first generation of the Prion-Like Amino Acid Composition (PLAAC) algorithm led to the discovery of new prions (11), while application of PAPA to this set of candidate PrLDs markedly improved the discrimination between domains with and without prion activity in vivo (7,14). Similarly, PLAAC identifies a number of PrLDs within the human proteome, and aggregation of these proteins is associated with an assortment of muscular and neurological disorders (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34). In some cases, increases in aggregation propensity due to single amino acid substitutions are accurately predicted by multiple aggregation prediction algorithms, including PAPA (33,35).…”