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
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DOI：
10.1186/s40478-018-0528-y
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发表时间：
2018-04-13
影响因子：
7.1
通讯作者：
Appel, Stanley H.
中科院分区：
文献类型：
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作者：
Cykowski, Matthew D.;Powell, Suzanne Z.;Appel, Stanley H.
肌萎缩伴无力是肌萎缩侧索硬化症（ALS）的核心特征，长期以来一直被认为是运动神经元丢失所致。然而，在ALS患者中进行的几项研究，以及在动物模型中进行的更多研究，对这一假设提出了挑战，后者提供了肌肉在疾病中发挥积极作用的直接证据。在这里，我们研究了来自57名ALS患者的148个骨骼肌样本中细胞自主病理学的可能作用，确定了19名患者（33.3%）和24个组织样本（16.2%的标本）的肌纤维中磷酸化TAR DNA结合蛋白（pTDP-43）夹杂物。确定了肌群特异性差异，pTDP-43病理学在轴肌（棘旁肌、横膈膜）中明显比在非轴肌中更常见（P = 0.0087）。这种病理学与相关的临床、遗传（c9 ALS）或神经系统病理数据没有显着相关性，表明它不限于ALS患者的任何特定亚组。在25个非ALS肌肉样品中，pTDP-43包涵体仅见于自噬相关疾病包涵体肌炎（IBM）（n = 4），其中它们比阳性ALS样品中更弥散（P = 0.007）。与IBM样品一样，ALS中的pTDP-43聚集体是p62/螯合体-1阳性的，可能表明诱导了自噬。磷酸化TDP-43阳性ALS和IBM样品也显示出TARDBP和SQSTM 1表达的显著上调。这些发现暗示在一些ALS患者中，包括散发性和家族性病例，中轴骨骼肌是pTDP-43病理学的额外部位，这值得进一步研究。
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.