TDP-43 in skeletal muscle of patients affected with amyotrophic lateral sclerosis

Sorarù, Gianni; Orsetti, Valeria; Buratti, Emanuele; Baralle, Francisco E.; Cima, Valentina; Volpe, M; D’Ascenzo, Carla; Palmieri, Arianna; Koutsikos, Kostantinos; Pegoraro, Elena; Angelini, C.

doi:10.3109/17482960902810890

Cited by 20 publications

(17 citation statements)

References 19 publications

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“…This implicates axial skeletal muscle as an additional site of pTDP-43 pathology in ALS. A muscle group-specific difference in muscle pathology was also suggested by the finding that pTDP-43 inclusions were significantly more frequent in samples from axial muscle groups than appendicular groups (the absence of inclusion pathology in quadriceps samples is also consistent with the negative result of an earlier study [ 50 ] that did not assess axial muscle groups). Our finding that pTDP-43-positive (FUS-negative) aggregates in ALS samples are also positive for the autophagy pathway protein p62/ sequestosome-1 suggests the possibility of an engagement of endogenous autophagic mechanisms in ALS muscle, as in motor neurons.…”

Section: Discussionsupporting

confidence: 65%

“…Studies of protein aggregates in human ALS muscle, that might indicate cell autonomous pathology, are much more limited. One study of 30 quadriceps biopsies did not identify pTDP-43 pathology in any samples [ 50 ]. Another recent study of deltoid samples found p62-positive, pTDP-43-negative inclusions [ 2 ] and p62-positive, pTDP-43-negative inclusions were recently described in the gastrocnemius of a single c9ALS patient [ 53 ].…”

Section: Introductionmentioning

confidence: 99%

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

Cykowski

Powell

Appel

et al. 2018

acta neuropathol commun

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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.

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Section: Discussionsupporting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

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

Cykowski

Powell

Appel

et al. 2018

acta neuropathol commun

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“…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).…”

Section: Tdp43mentioning

confidence: 99%

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

Picchiarelli¹,

Dupuis²

2020

CST

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A number of neuromuscular and muscular diseases, including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and several myopathies, are associated to mutations in related RNA-binding proteins (RBPs), including TDP-43, FUS, MATR3 or hnRNPA1/B2. These proteins harbor similar modular primary sequence with RNA binding motifs and low complexity domains, that enables them to phase separate and create liquid microdomains. These RBPs have been shown to critically regulate multiple events of RNA lifecycle, including transcriptional events, splicing and RNA trafficking and sequestration. Here, we review the roles of these disease-related RBPs in muscle and motor neurons, and how their dysfunction in these cell types might contribute to disease.

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“…These are intriguing findings since they might offer the possibility of developing a diagnostic ante mortem assay and a biomarker to monitor responses to new interventions in clinical trials, but these studies need to be extended and the findings verified in larger patient and control cohorts, especially through post mortem follow‐up studies. However, skeletal muscle of ALS patients, another potential ante mortem diagnostic approach, has been shown to be devoid of pathological TDP‐43 99 …”

Section: Biomarkers Of Pathological Tdp‐43mentioning

confidence: 99%

Amyotrophic lateral sclerosis and frontotemporal lobar degeneration: A spectrum of TDP-43 proteinopathies

Geser¹,

Lee²,

Trojanowski³

2010

Neuropathology

179

142

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It is now established that pathological transactive response DNA-binding protein with a Mr of 43 kD (TDP-43) on sodium dodecyl sulfate-polyacrylamide gel electrophoresis is the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitin-positive inclusions (now known as FTLD-TDP). In fact, the discovery of pathological TDP-43 solidified the idea that these disorders are multi-system diseases and this led to the concept of a TDP-43 proteinopathy as a spectrum of disorders comprised of different clinical and pathological entities extending from ALS to ALS with cognitive impairment/dementia and FTLD-TDP without or with motor neuron disease (FTLD-MND). These align along a broad disease continuum sharing similar pathogenetic mechanisms linked to pathological TDP-43. We here review salient findings in the development of a concept of TDP-43 proteinopathy as a novel group of neurodegenerative diseases similar in concept to α-synucleinopathies and tauopathies.

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TDP-43 in skeletal muscle of patients affected with amyotrophic lateral sclerosis

Cited by 20 publications

References 19 publications

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

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

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

Amyotrophic lateral sclerosis and frontotemporal lobar degeneration: A spectrum of TDP-43 proteinopathies

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