TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle

Abstract

SummaryA dominant histopathological feature in neuromuscular diseases including amyotrophic lateral sclerosis and inclusion body myopathy is cytoplasmic aggregation of the RNA-binding protein TDP-43. Although rare protein-misfolding mutations in TDP-43 often cause protein aggregation, most patients do not have a TDP-43 mutation suggesting aggregates of wild-type TDP-43 arise by an unknown mechanism. Here we show TDP-43 is an essential protein for normal skeletal muscle formation that unexpectedly forms cytoplasmic, amyloid-like oligomeric assemblies, termed myo-granules, during skeletal muscle regeneration in mice and humans. Myo-granules bind mRNAs encoding sarcomeric proteins and are cleared as myofibers mature. Although myo-granules occur during normal skeletal muscle regeneration, myo-granules can seed TDP-43 amyloid fibrils in vitro, and are increased in a mouse model of inclusion body myopathy. Therefore, heightened assembly or decreased clearance of functionally normal myo-granules could be the source of cytoplasmic TDP-43 aggregates common to neuromuscular disease.

Pleiotropic requirements for human TDP-43 in the regulation of cell and organelle homeostasis

“…Identifying human genes affected by cryptic exon insertion arising from TDP-43 dysfunction and understanding the consequences of their disruption is thus important for understanding both the normal mechanisms whereby TDP-43 ensures splicing fidelity as well as the contributions of aberrant mRNA splicing to disease pathology. In addition to regulating mRNA splicing, TDP-43 has also been implicated in the regulation of other aspects of RNA biology including: transcription, microRNA processing, RNA stability and regulation of cytoplasmic ribonucleoprotein complexes such as stress granules, myo-granules involved in muscle regeneration and granules involved in axonal RNA transport in neurons (Gopal et al, 2017;Ratti and Buratti, 2016;Vogler et al, 2018).…”

Shared regulatory pathways reveal novel genetic correlations between grip strength and neuromuscular disorders

“…In ALS, skeletal muscle harbours the characteristic protein aggregates (composed principally of TDP-43) [15] whose burden in the CNS predicts neurodegeneration [16,17]. In muscle, these TDP-43 protein aggregates may disrupt the transport of mRNAs essential for muscle fibre regeneration [18,19]. Together these findings support a direct contribution of skeletal muscle to the ALS phenotype.…”

“…Overall, 179, 18, 286 and 135 SNPs were associated with GS, MG, MS and, ALS, respectively, at a suggestive level of significance (p ≤ 5x10 -6 ). Using the CoDeS3D algorithm [40], we mapped spatial regulatory connections between each phenotype-associated SNP and one or more gene coding regions (GENCODE release 19). For each SNP-gene pair, spatial contacts were identified from existing Hi-C [38] chromatin contact data derived from eight immortalized cell lines representing human germ layer lineages (GM12878, IMR90, HMEC, NHEK, K562, HUVEC, HeLa and KBM7) [41] and one tissue (Psoas muscle) [42] (Table S1).…”

Cdc48/VCP and endocytosis regulate TDP-43 and FUS toxicity and turnover

“…Under conditions of cellular stress, both TDP-43 and FUS re-localize into cytoplasmic stress granules (SGs) [6,7], which are dynamic mRNA-protein assemblies implicated in regulating mRNA function [8,9]. Given this, and in light of ALS-associated mutations that generally reduce SG dynamics, SGs have been theorized to promote formation of TDP-43 and FUS aggregates that are observed in ALS patients [10,11], though recent studies suggest SG-independent aggregation mechanism also likely exist [12][13] [14]. Regardless, various studies indicate that TDP-43 and FUS aggregates, or simply excessive cytoplasmic localization of TDP-43 or FUS, may result in a toxic gain of function that leads to motor-neuron degeneration [15][16][17][18][19] [20,21].…”