The Ubiquitin Proteasome System in Neuromuscular Disorders: Moving Beyond Movement

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.

Prenatal Skeletal Muscle Transcriptome Analysis Reveals Novel MicroRNA-mRNA Networks Associated with Intrauterine Growth Restriction in Pigs

“…Additionally, the most enriched pathway by upregulated genes is ubiquitin-mediated proteolysis ( Figure 7 B). Bachiller et al recently reviewed ubiquitin-mediated proteolysis in several skeletal muscle disorders including muscle atrophy, defective growth of neuromuscular junction, nemaline myopathy, and reduced proliferation, and differentiation of myoblasts [ 96 ]. We suggest that dysregulation of metabolic pathways and upregulation of the ubiquitin pathway in skeletal muscles is not only associated with the pathophysiology of IUGR, but can also cause severe complications after birth and contribute toward increased morbidity and mortality in IUGR-affected piglets.…”

Assessment of Weighted Gene Co-Expression Network Analysis to Explore Key Pathways and Novel Biomarkers in Muscular Dystrophy

“…Hence, dysfunction of the ubiquitin proteasome machinery could contribute to muscle pathologies. 43 , 44 Nevertheless, most lines of evidence are directly linked to DMD rather than BMD. Altered levels of proteasome and ubiquitin were discovered in the cytoplasm of necrotic fibers from patients with DMD.…”

Exocyst-mediated membrane trafficking of the lissencephaly-associated ECM receptor dystroglycan is required for proper brain compartmentalization

“…Moreover, in vertebrates, Dg phosphorylation has been identified as a possible signal to promote the proteasomal degradation of the entire DGC ( Gazzerro et al, 2010 ; Lipscomb et al, 2016 ; Miller et al, 2012 ; Signorino et al, 2018 ). Therefore, by preventing phosphorylation of Dg or inhibiting ubiquitination or proteasomal degradation, the DGC is stabilized ( Bachiller et al, 2020 ; ENMC DGpathy Study Group et al, 2017 ). Studies in mice and zebrafish myoblasts and muscles have established that pharmacological treatment with proteasome or tyrosine kinase inhibitors can increase levels of non-phosphorylated Dg, which ameliorates the dystrophic phenotype ( Lipscomb et al, 2016 ; Vélez-Aguilera et al, 2018 ).…”