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    • The molecular mechanisms that mediate the plasticity of the

    2023-09-26

    The molecular mechanisms that mediate the plasticity of the NMJ are not well understood. PGC-1α is a master regulator of the NMJ gene expression program 23, 24, and thus AMPK might indirectly regulate the NMJ via its broad influence on the coactivator. Cerveró et al.[6] recently provided more direct evidence for a role of AMPK in regulating the NMJ. The authors observed that chronic AICAR administration to SMA mice mitigated the gross simplification of the postsynaptic specialization. Interestingly, AMPK activation also corrected several metrics of the abnormal presynaptic apparatus. Additional support for a role of AMPK in maintaining and remodeling neuromuscular synapses was revealed by Samuel and colleagues [25] who were the first to demonstrate that the AMPK pathway directly regulates synaptic plasticity. In this elegant study, the authors observed that aging-induced remodeling of retinal synapses was associated with reductions in the expression and activity of AMPK and its upstream kinase liver kinase B1 (LKB1). Furthermore, these synapses in young mice that were deficient in either AMPK or LKB1 were virtually indistinguishable from the retinal synapses in old, WT animals. Genetically or pharmacologically increasing AMPK activity mitigated the age-related synaptic alterations. Thus, while its role in skeletal muscle is better understood, emerging evidence strongly suggests that AMPK also regulates remodeling of the NMJ. All AMPK subunits, except for γ3, are expressed in mouse spinal cord (SC) αMNs 26, 27. However, to our knowledge, specific AMPK heterotrimer composition abundance has not yet been detailed in αMNs. Addressing this knowledge gap represents an important opportunity to further increase our understanding of the kinases tissue-specific expression pattern. Phosphorylated AMPK can also be found within αMNs in mice in vivo[28], and possibly within human samples as well 7, 8. The functional consequences of AMPK activation in αMNs are revealed when examined in models of the NMD amyotrophic lateral sclerosis (ALS). Liu and colleagues 7, 8 recently observed that the cytoplasmic mislocalization of RNA-binding proteins (RBPs), human antigen R, and TAR DNA-binding protein 43 (TDP-43) was accompanied by augmented levels of phosphorylated AMPK in αMNs of ALS patients. AMPK activity in αMNs and SC also correlates with progression in mutant superoxide dismutase 1 (SOD1)-mediated disease 27, 28, 29. By contrast, reduced AMPK activity was found in αMNs and SC of TDP-43 transgenic mice and immortalized neuroblastoma SC MN-like hybrid BMS 193885 mg expressing TDP-43 mutants [28]. Therefore, mutant SOD1 and TDP-43 exert contrasting effects on AMPK biology that may reflect key differences in neurodegeneration in αMNs and SC of SOD1 versus TDP-43 ALS. To further add to the complexity, chronic pharmacological AMPK stimulation with either latrepirdine or resveratrol delayed symptom onset, preserved αMN function and survival, and significantly increased life span in SOD1 ALS mice 29, 30. Thus, although AMPK clearly controls facets of αMN biology, the role of the kinase appears enigmatic but sophisticated, and therefore requires continued investigation to more clearly understand its function in these cells. In total, the evidence for AMPK-mediated regulation of skeletal muscle, NMJ, and αMN phenotypes provides compelling rationale for investigating the therapeutic capabilities of the kinase in the most prevalent inherited or acquired NMDs.
    AMPK as a Therapeutic Target in DMD DMD is the most prevalent genetically inherited NMD, affecting one in about 3500 live male births [31]. DMD is life limiting, with death usually occurring by the third decade due to cardiopulmonary compromise [31]. The causative gene of DMD encodes the protein dystrophin, which is a structural molecule that links the cytoskeleton to the sarcolemma of muscle fibers. Mutations in the DMD gene result in the loss of functional dystrophin protein and the improper assembly of its larger oligomeric complex [32]. This aggregation of sarcolemmal proteins is known as the dystrophin-associated protein complex (Figure 1A,B). Consequently, these alterations result in the destruction of myofibers by necrosis and apoptosis, and in combination with the inevitable inability of the damaged tissue to regenerate [32], ultimately lead to muscle wasting and death in DMD. Glucocorticoids (GCs) significantly delay the decline in muscle strength and function, and prolong ambulation and pulmonary function but are accompanied by detrimental side effects [31]. Two pharmacological strategies, one employing antisense oligonucleotide (ASO)-mediated exon skipping and the other small molecule-evoked suppression of premature termination codons, likely represent the first generation of applied gene therapy technologies for this disorder 33, 34. The dystrophic pathology may also be mitigated through upregulation of the dystrophin homolog utrophin, in conjunction with the utrophin-associated protein complex (UAPC)5, 35. Further research is necessary to identify therapeutic targets that would act to mitigate muscular dystrophy via multiple, complementary cellular pathways, and most critically, be effective in all DMD patients regardless of their specific mutation.