| Autor: |
Cykowski MD; Department of Pathology and Genomic Medicine, Houston Methodist Hospital, 6565 Fannin Street, Houston, TX, 77030, USA. mdcykowski@houstonmethodist.org.; Institute of Academic Medicine (IAM) in the Houston Methodist Research Institute (HMRI), Houston Methodist Hospital, 6565 Fannin Street, Houston, TX, 77030, USA. mdcykowski@houstonmethodist.org., Powell SZ; Department of Pathology and Genomic Medicine, Houston Methodist Hospital, 6565 Fannin Street, Houston, TX, 77030, USA.; Institute of Academic Medicine (IAM) in the Houston Methodist Research Institute (HMRI), Houston Methodist Hospital, 6565 Fannin Street, Houston, TX, 77030, USA.; Houston Methodist Neurological Institute, Houston Methodist Hospital, 6565 Fannin Street, Houston, TX, 77030, USA., Appel JW; Houston Methodist Neurological Institute, Houston Methodist Hospital, 6565 Fannin Street, Houston, TX, 77030, USA.; Department of Neurology, Houston Methodist Hospital, 6565 Fannin Street, Houston, TX, 77030, USA., Arumanayagam AS; Department of Pathology and Genomic Medicine, Houston Methodist Hospital, 6565 Fannin Street, Houston, TX, 77030, USA., Rivera AL; Department of Pathology and Genomic Medicine, Houston Methodist Hospital, 6565 Fannin Street, Houston, TX, 77030, USA.; Institute of Academic Medicine (IAM) in the Houston Methodist Research Institute (HMRI), Houston Methodist Hospital, 6565 Fannin Street, Houston, TX, 77030, USA.; Houston Methodist Neurological Institute, Houston Methodist Hospital, 6565 Fannin Street, Houston, TX, 77030, USA., Appel SH; Institute of Academic Medicine (IAM) in the Houston Methodist Research Institute (HMRI), Houston Methodist Hospital, 6565 Fannin Street, Houston, TX, 77030, USA.; Houston Methodist Neurological Institute, Houston Methodist Hospital, 6565 Fannin Street, Houston, TX, 77030, USA.; Department of Neurology, Houston Methodist Hospital, 6565 Fannin Street, Houston, TX, 77030, USA. |
| Abstrakt: |
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. |
