Abstract
Neuromuscular disorders (NMDs) affect 1 in 3000 people worldwide. There are more than 150 different types of NMDs, where the common feature is the loss of muscle strength. These disorders are classified according to their neuroanatomical location, as motor neuron diseases, peripheral nerve diseases, neuromuscular junction diseases, and muscle diseases. Over the years, numerous studies have pointed to protein homeostasis as a crucial factor in the development of these fatal diseases. The ubiquitin–proteasome system (UPS) plays a fundamental role in maintaining protein homeostasis, being involved in protein degradation, among other cellular functions. Through a cascade of enzymatic reactions, proteins are ubiquitinated, tagged, and translocated to the proteasome to be degraded. Within the ubiquitin system, we can find three main groups of enzymes: E1 (ubiquitin-activating enzymes), E2 (ubiquitin-conjugating enzymes), and E3 (ubiquitin–protein ligases). Only the ubiquitinated proteins with specific chain linkages (such as K48) will be degraded by the UPS. In this review, we describe the relevance of this system in NMDs, summarizing the UPS proteins that have been involved in pathological conditions and neuromuscular disorders, such as Spinal Muscular Atrophy (SMA), Charcot–Marie–Tooth disease (CMT), or Duchenne Muscular Dystrophy (DMD), among others. A better knowledge of the processes involved in the maintenance of proteostasis may pave the way for future progress in neuromuscular disorder studies and treatments.
Highlights
Neuromuscular disorders (NMDs) consist of a heterogeneous group of diseases, including more than 150 different types
Several studies have revealed the fundamental role of the ubiquitin–proteasome system (UPS) on disorders, including NMDs (spinal muscular atrophy (SMA), spinal and bulbar muscular atrophy (SBMA), X-spinal muscular atrophy, X-linked juvenile and adult-onset amyotrophic lateral sclerosis (ALS) [5,6,7,8,9]), and peripheral neuropathies (Charcot–Marie–Tooth (CMT) disease [10,11,12])
Reduced levels or abnormal functionality leads to loss of ubiquitination and accumulation of tripartite motif-containing protein (TRIM) substrates within the muscle fibers
Summary
Neuromuscular disorders (NMDs) consist of a heterogeneous group of diseases, including more than 150 different types. They affect mainly the peripheral nervous system (PNS), skeletal muscle, neuromuscular junctions (NMJ), and spinal cord (SC). Several studies have revealed the fundamental role of the UPS on disorders (for review see [4]), including NMDs (spinal muscular atrophy (SMA), spinal and bulbar muscular atrophy (SBMA), X-spinal muscular atrophy, X-linked juvenile and adult-onset amyotrophic lateral sclerosis (ALS) [5,6,7,8,9]), and peripheral neuropathies (Charcot–Marie–Tooth (CMT) disease [10,11,12]). We compile for the first time the importance of the UPS in neuromuscular function and its implication in pathological conditions
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