Beyond motor neurons: peripheral TDP-43 pathology in skeletal muscle and intramuscular nerves in amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by accumulation of the 43-kDa TAR DNA-binding protein (TDP-43). This neuropathological signature has been well documented within the CNS; however, recent findings indicate that the phosphorylated TDP-43 additionally deposits in peripheral tissues, including skeletal muscle and intramuscular nerves. These data warrant a change of view from a neurocentric perspective of ALS pathogenesis toward a broader concept of TDP-43 proteinopathy extending both within and beyond the nervous system.

In this review, we focus on current evidence supporting the presence of TDP-43 pathology in ALS skeletal muscle, examining its topographic distribution, molecular characteristics, and associations with intramuscular nerve bundles. We also discuss the susceptibility of intrinsic muscle cells, disrupted axonal transport, and impairment in protein quality control. Phosphorylated TDP-43 pathology in muscle biopsies from ALS patients has emerged as a promising tool in the early diagnosis of the disease. Moreover, we discuss the relevance of these findings to ALS pathogenesis and potential therapeutic implications.