Phosphorylated TDP-43 (pTDP-43) aggregates in the axial skeletal muscle of patients with sporadic and familial amyotrophic lateral sclerosis

Abstract

Muscle atrophy with weakness is a core feature of amyotrophic lateral sclerosis (ALS) that has long been attributed to motor neuron loss alone. However, several studies in ALS patients, and more so in animal models, have challenged this assumption with the latter providing direct evidence that muscle can play an active role in the disease. Here, we examined the possible role of cell autonomous pathology in 148 skeletal muscle samples from 57 ALS patients, identifying phosphorylated TAR DNA-binding protein (pTDP-43) inclusions in the muscle fibers of 19 patients (33.3%) and 24 tissue samples (16.2% of specimens). A muscle group-specific difference was identified with pTDP-43 pathology being significantly more common in axial (paraspinous, diaphragm) than appendicular muscles (P = 0.0087). This pathology was not significantly associated with pertinent clinical, genetic (c9ALS) or nervous system pathologic data, suggesting it is not limited to any particular subgroup of ALS patients. Among 25 non-ALS muscle samples, pTDP-43 inclusions were seen only in the autophagy-related disorder inclusion body myositis (IBM) (n = 4), where they were more diffuse than in positive ALS samples (P = 0.007). As in IBM samples, pTDP-43 aggregates in ALS were p62/ sequestosome-1-positive, potentially indicating induction of autophagy. Phospho-TDP-43-positive ALS and IBM samples also showed significant up-regulation of TARDBP and SQSTM1 expression. These findings implicate axial skeletal muscle as an additional site of pTDP-43 pathology in some ALS patients, including sporadic and familial cases, which is deserving of further investigation.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0528-y) contains supplementary material, which is available to authorized users.

TDP-43 promotes the formation of neuromuscular synapses through the regulation of Disc-large expression in Drosophila skeletal muscles

“…This supports the idea that ALS may have a nonneuronal origin [11]. In consonance with this hypothesis, pathological modifications of TDP-43 have been found in the skeletal muscles of patients with different neuromuscular diseases such as inclusion body myositis (IBM) and sporadic, familial forms of ALS [12]. Likewise, overexpression of TDP-43 leads to age-related muscle weakness and degeneration in mice [13], zebrafish [14], and Drosophila [15,16], suggesting that the regulation of TDP-43 function could play an important role in muscle physiology.…”

Role of RNA Binding Proteins with prion-like domains in muscle and neuromuscular diseases

“…This importance of TDP43 in muscle function indirectly suggests that this protein could be involved in muscle dysfunction in human diseases. Indeed, muscle cytoplasmic aggregates of TDP43 were observed in patients with ALS, muscle dystrophy and inclusion body myositis (IBM) [60][61][62][63][64][65][66][67][68]. TDP43 might also indirectly participate in muscle pathology developed during inherited peripheral neuropathies of myofibrillar myopathies [69] (Figure 2).…”

Inflammatory profiles relate to survival in subtypes of amyotrophic lateral sclerosis

“…16,29 Of interest, phosphorylated TDP-43 may be identified in the skeletal muscle of patients with ALS as in patients with inclusion body myositis. 30 A study reported that exposure of microglial cells to TDP-43 aggregates resulted in the secretion of proinflammatory cytokines including TNF-α and IL-1β, which suggests that TDP-43-mediated signaling contribute to microglial neurotoxic activation in ALS. 31 Another recent study of C9orf72HRE knock-in mice highlighted increased innate immune signaling without mentioning specific cytokines/pathways, but IL-1β is central in innate immunity, and produced by all CNS-resident cells downstream of inflammasome signaling.…”