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

Matthew D Cykowski,Stanley H Appel,Joan W Appel,Anithachristy S Arumanayagam,Suzanne Z Powell,Andreana L Rivera

doi:10.1186/s40478-018-0528-y

Matthew D Cykowski, Stanley H Appel + Show 4 more

Open Access

https://doi.org/10.1186/s40478-018-0528-y

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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.

Highlights

amyotrophic lateral sclerosis (ALS) is a progressive disorder characterized by motor neuron injury, muscle weakness, bulbar symptoms, such as dysarthria and dysphagia [1], and frontalsubcortical cognitive dysfunction in many patients [43, 44]
To further examine whether cell autonomous pathology is present in the muscle of human ALS patients, we studied 148 muscle specimens from 57 patients to identify the prevalence and muscle group distribution of phosphorylated TAR DNA-binding protein 43 kDA (pTDP-43), a well-characterized marker of ALS pathology in motor neurons
Ten patients had a history of family history of ALS (fALS) (17.5%) and the remaining cases were sporadic (n = 45, 79%), or family history was unknown (n = 2). C9ORF72 expansionassociated ALS (c9ALS) was present in 13 patients (22.8%), accounting for 90% of the clinically designated fALS patients in this study and 4 sporadic ALS (sALS) patients (8.9% of sALS cases)

Summary

Introduction

ALS is a progressive disorder characterized by motor neuron injury, muscle weakness, bulbar symptoms, such as dysarthria and dysphagia [1], and frontalsubcortical cognitive dysfunction in many patients [43, 44]. Pathologic studies of ALS nervous tissue have emphasized cell autonomous and non-cell autonomous pathologies in upper and lower motor neuron groups, and more recently, in non-motor brain regions [18, 38]. These include neuronal and glial inclusions comprising misfolded and phosphorylated TAR DNA-binding protein 43 kDA (pTDP-43) [10, 17, 35] and fused-in-sarcoma (FUS) protein [34], as well as dipeptide repeat pathology in C9ORF72 expansionassociated ALS (c9ALS) [54]. The critical role of glia and immune cells in disease progression is recognized in human ALS and transgenic ALS models [26, 40, 58].

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