Drosophila models of oculopharyngeal muscular dystrophy (OPMD) included in study seeking therapeutic strategies for treating prion diseases

Neurotherapeutics. 2021 Feb 2. doi: 10.1007/s13311-020-00992-6

Anti-prion Drugs Targeting the Protein Folding Activity of the Ribosome Reduce PABPN1 Aggregation

Bamia A, Sinane M, Naït-Saïdi R, Dhiab J, Keruzoré M, Nguyen PH, Bertho A, Soubigou F, Halliez S, Blondel M, Trollet C, Simonelig M, Friocourt G, Béringue V, Bihel F, Voisset C

From the abstract: Prion diseases are caused by the propagation of PrPSc, the pathological conformation of the PrPC prion protein ... and no therapeutic solution is currently available. We thus sought to identify new anti-prion molecules and found that flunarizine inhibited PrPSc propagation in cell culture and significantly prolonged survival of prion-infected mice. Using an in silico therapeutic repositioning approach based on similarities with flunarizine chemical structure, we tested azelastine, duloxetine, ebastine, loperamide and metixene and showed that they all have an anti-prion activity. ... Strikingly, some of these drugs were also able to alleviate phenotypes due to PABPN1 nuclear aggregation in cell and Drosophila models of oculopharyngeal muscular dystrophy (OPMD). These data emphasize the therapeutic potential of anti-PFAR drugs for neurodegenerative and neuromuscular proteinopathies.

DOI: 10.1007/s13311-020-00992-6
PMID: 33533011

Drosophila model of Freeman-Sheldon Syndrome points to possible molecular mechanism undlerying effects of the syndrome on muscles

Biophys J. 2021 Jan 29:S0006-3495(21)00075-8. doi: 10.1016/j.bpj.2020.12.033.

Prolonged Myosin Binding Increases Muscle Stiffness in Drosophila Models of Freeman-Sheldon Syndrome.

Bell KM, Huang A, Kronert WA, Bernstein SI, Swank DM

Abstract: Freeman-Sheldon Syndrome (FSS) is characterized by congenital contractures resulting from dominant point mutations in the embryonic isoform of muscle myosin. To investigate its disease mechanism, we used Drosophila models expressing FSS myosin mutations Y583S or T178I in their flight and jump muscles. We isolated these muscles from heterozygous mutant Drosophila and performed skinned fiber mechanics. The most striking mechanical alteration was an increase in active muscle stiffness. Y583S/+ and T178I/+ fibers' elastic moduli increased 70% and 77%, respectively. Increased stiffness contributed to decreased power generation, 49% and 66%, as a result of increased work absorbed during the lengthening portion of the contractile cycle. Slower muscle kinetics also contributed to the mutant phenotype, as shown by 17% and 32% decreases in optimal frequency for power generation, and 27% and 41% slower muscle apparent rate constant 2πb. Combined with previous measurements of slower in vitro actin motility, our results suggest a rate reduction of at least one strongly-bound cross-bridge cycle transition that increases the time myosin spends strongly bound to actin, ton. Increased ton was further supported by decreased ATP affinity and a 16% slowing of jump muscle relaxation rate in T178I heterozygotes. Impaired muscle function caused diminished flight and jump ability of Y583S/+ and T178I/+ Drosophila. Based on our results, assuming that our model system mimics human skeletal muscle, we propose that one mechanism driving FSS is elevated muscle stiffness arising from prolonged ton in developing muscle fibers.

DOI: 10.1016/j.bpj.2020.12.033
PMID: 33524372