PDE10A Inhibition Reduces the Manifestation of Pathology in DMD Zebrafish and Represses the Genetic Modifier PITPNA

Lambert, Matthias; Spinazzola, Joseph; Widrick, Jeffrey J.; Pakula, Anna; Conner, James; Chin, Janice E.; Owens, Jane; Kunkel, Louis M.

doi:10.1016/j.ymthe.2020.11.021

Cited by 9 publications

(2 citation statements)

References 94 publications

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“…In this study, 23 molecules were selected for a nutraceutical screening either on the basis of their role as phosphodiesterase inhibitors, which have a known anti-inflammatory action on muscle, or because they are antioxidants known to counteract enhanced free radical production [30]. Mortality, improved locomotion, and a reduced number of larvae with impaired birefringence were taken as efficacy endpoints [31].…”

Section: Discussionmentioning

confidence: 99%

Nutraceutical Screening in a Zebrafish Model of Muscular Dystrophy: Gingerol as a Possible Food Aid

et al. 2021

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Duchenne muscular dystrophy (DMD), caused by mutations in the dystrophin gene, is an inherited neuromuscular disorder that causes loss of muscle mass and motor skills. In the era of genomic medicine, there is still no known cure for DMD. In clinical practice, there is a growing awareness of the possible importance of nutrition in neuromuscular diseases. This is mostly the result of patients’ or caregivers’ empirical reports of how active substances derived from food have led to improved muscle strength and, thus, better quality of life. In this report, we investigate several nutraceutical principles in the sapje strain of zebrafish, a validated model of DMD, in order to identify possible natural products that, if supplemented in the diet, might improve the quality of life of DMD patients. Gingerol, a constituent of fresh ginger, statistically increased the locomotion of mutant larvae and upregulated the expression of heme oxygenase 1, a target gene for therapy aimed at improving dystrophic symptoms. Although three other compounds showed a partial positive effect on locomotor and muscle structure phenotypes, our nutraceutical screening study lent preliminary support to the efficacy and safety only of gingerol. Gingerol could easily be proposed as a dietary supplement in DMD.

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Section: Discussionmentioning

confidence: 99%

Nutraceutical Screening in a Zebrafish Model of Muscular Dystrophy: Gingerol as a Possible Food Aid

et al. 2021

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“…Using the zebrafish dystrophin-deficient model, an inhibitor of the phosphodiesterase 10A (PDE10A) was found to reduce the manifestation of the dystrophic muscle phenotype. Moreover, PDE10A inhibition in zebrafish and in DMD patient-derived myoblasts were also associated with reduction of PITPα expression [ 99 ]. Thus, these results indicate a reduction in PITPα as a protective genetic modifier in dystrophin-deficient model systems and permits the escape of the dystrophic phenotype.…”

Section: Class I Pitpsmentioning

confidence: 99%

Courier service for phosphatidylinositol: PITPs deliver on demand

Ashlin

Blunsom

Cockcroft

2021

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Phosphatidylinositol is the parent lipid for the synthesis of seven phosphorylated inositol lipids and each of them play specific roles in numerous processes including receptor-mediated signalling, actin cytoskeleton dynamics and membrane trafficking. PI synthesis is localised to the endoplasmic reticulum (ER) whilst its phosphorylated derivatives are found in other organelles where the lipid kinases also reside. Phosphorylation of PI to phosphatidylinositol (4,5) bisphosphate (PI(4,5)P 2 ) at the plasma membrane and to phosphatidylinositol 4-phosphate (PI4P) at the Golgi are key events in lipid signalling and Golgi function respectively. Here we review a family of proteins, phosphatidylinositol transfer proteins (PITPs), that can mobilise PI from the ER to provide the substrate to the resident kinases for phosphorylation. Recent studies identify specific and overlapping functions for the three soluble PITPs (PITPα, PITPβ and PITPNC1) in phospholipase C signalling, neuronal function, membrane trafficking, viral replication and in cancer metastases.

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