ABSTRACT
Welander distal myopathy (WDM) is a muscle dystrophy characterized by adult-onset distal muscle weakness, prevalently impacting the distal long extensors of the hands and feet. WDM is an autosomal dominant disorder caused by a missense mutation (c.1362G>A; p.E384K) in the TIA1 (T-cell intracellular antigen 1) gene, which encodes an RNA-binding protein basically required for the posttranscriptional regulation of RNAs. We have developed a heterologous cell model of WDM to study the molecular and cellular events associated with mutated TIA1 expression. Specifically, we analyzed how this mutation affects three regulatory functions mediated by TIA1: (i) control of alternative SMN2 (survival motor neuron 2) splicing; (ii) formation, assembly, and disassembly of stress granules; and (iii) mitochondrial dynamics and its consequences for mitophagy, autophagy, and apoptosis. Our results show that whereas WDM-associated TIA1 expression had only a mild effect on SMN2 splicing, it led to suboptimal adaptation to environmental stress, with exacerbated stress granule formation that was accompanied by mitochondrial dysfunction and autophagy. Overall, our observations indicate that some aspects of the cell phenotype seen in muscle of patients with WDM can be recapitulated by ectopic expression of WDM-TIA1 in embryonic kidney cells, highlighting the potential of this model to investigate the pathogenesis of this degenerative disease and possible therapeutics.
