The P2X7 purinoceptor in pathogenesis and treatment of dystrophino- and sarcoglycanopathies

Dystrophinopathy and sarcoglycanopathies are incurable diseases caused by mutations in the genes encoding dystrophin or members of the dystrophin associated protein complex (DAPC). Restoration of the missing dystrophin or sarcoglycans via genetic approaches is complicated by the downsides of persona...

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Bibliographic Details
Published in:	Current opinion in pharmacology Vol. 69; p. 102357
Main Authors:	Gόrecki, Dariusz C., Rumney, Robin M.H.
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01-04-2023
Subjects:	Adenosine Triphosphate - metabolism Animals Dystrophin Mice Muscle, Skeletal - metabolism Receptors, Purinergic P2X7 - metabolism Sarcoglycanopathies - metabolism Sarcoglycanopathies - pathology Sarcoglycans - genetics Sarcoglycans - metabolism
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Summary:	Dystrophinopathy and sarcoglycanopathies are incurable diseases caused by mutations in the genes encoding dystrophin or members of the dystrophin associated protein complex (DAPC). Restoration of the missing dystrophin or sarcoglycans via genetic approaches is complicated by the downsides of personalised medicines and immune responses against re-expressed proteins. Thus, the targeting of disease mechanisms downstream from the mutant protein has a strong translational potential. Acute muscle damage causes release of large quantities of ATP, which activates P2X7 purinoceptors, resulting in inflammation that clears dead tissues and triggers regeneration. However, in dystrophic muscles, loss of α-sarcoglycan ecto-ATPase activity further elevates extracellular ATP (eATP) levels, exacerbating the pathology. Moreover, seemingly compensatory P2X7 upregulation in dystrophic muscle cells, combined with high eATP leads to further damage. Accordingly, P2X7 blockade alleviated dystrophic damage in mouse models of both dystrophinopathy and sarcoglycanopathy. Existing P2X7 blockers could be re-purposed for the treatment of these highly debilitating diseases. •Loss of dystrophin and/or sarcoglycans reduces eATP degradation and enhances P2X7 signalling in muscles.•Sterile inflammation is a pathological hallmark of both DMD and sarcoglycanopathies.•Mitigation of this purinergic abnormality reduces damaging inflammation and improves the dystrophic phenotype.•P2X7 blockers could be rapidly re-purposed for treatment of DMD and sarcoglycanopathies.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-3 content type line 23 ObjectType-Review-1
ISSN:	1471-4892 1471-4973
DOI:	10.1016/j.coph.2023.102357