Evaluating proteasome modulation as a therapeutic strategy in nemaline myopathy
Wang, Jeffrey C.
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Nemaline myopathy is a subtype of congenital myopathy that is clinically characterized by muscle weakness and early hypotonia of variable severity. Pathologically, nemaline myopathy is characterized by the presence of nemaline rods that stain purple in modified Gӧmӧri trichrome dye in patient biopsies under a microscope. Affected individuals experience skeletal muscle weakness and feeding difficulties, but most individuals will also experience respiratory muscle weakness that is disproportional to the weakness in skeletal muscles. Currently, 6 different subtypes of nemaline myopathy have been identified, each caused by mutations in ACTA1, NEB, TPM2, TPM3, TNNT1, KBTBD13, CFL2, KLHL40, KLHL41, or LMOD3, which are genes that encode either thin filament proteins or Kelch-like proteins. Of these genes, mutations in NEB and ACTA1 account for the majority of nemaline myopathy cases. Due to the genetic heterogeneity of nemaline myopathy, it is imperative to discover therapeutic targets and treatments that can universally treat nemaline myopathy patients. Preliminary data from our lab has demonstrated that proteasome complexes are downregulated in nemaline myopathy patients. Further, proteasomal activators improved motor function in neb zebrafish models, demonstrating the potential for proteasome activators to be therapeutics for nemaline myopathy patients. To extend these studies, the effect of proteasome activators, betulinic acid and Rolipram, was evaluated on the motor function in neb zebrafish models. However, in our experimental trials with betulinic acid and Rolipram, no positive effect on motor function in neb zebrafish was observed. In order to confirm our findings for both betulinic acid and Rolipram, additional trials will need to be conducted.