Article ; Online: INAD and Duchenne muscular dystrophy, two ends of the iPLA2β spectrum.
2020 Volume 137, Page(s) 109589
Abstract: Infantile neuroaxonal dystrophy (INAD) and Duchenne muscular dystrophy (DMD) are two deadly neuromuscular degenerative diseases of childhood. Knowledge on their pathophysiological mechanisms may direct us towards treatment or a cure. Although these ... ...
| Abstract | Infantile neuroaxonal dystrophy (INAD) and Duchenne muscular dystrophy (DMD) are two deadly neuromuscular degenerative diseases of childhood. Knowledge on their pathophysiological mechanisms may direct us towards treatment or a cure. Although these diseases are caused by two totally different gene-mutations and cause different clinical pictures, in this article I propose a common disease mechanism in the two. This common mechanism is induced by defects in the response to cellular stress and injury. THE HYPOTHESIS: Depletion of iPLA2β in INAD and increased activity of iPLA2β in DMD eventually lead to similar defects in the response to cell stress and injury. According to this hypothesis, the depletion of iPLA2β in INAD primarily blocks repair mechanisms by the inability to form a mitochondrial permeability transition pore (PTP). Forming of the PTP is necessary to release mitochondrial coenzyme A (CoA) into the cytoplasm for activation of palmitoylation and massive endocytosis as a repair response. In DMD the increased activity of iPLA2β causes exhaustion of the stress signalling cascade by increased and prolonged PTP opening. Continuous leaking of mitochondrial CoA through the PTP leads to the inability of the cell to build a sufficient mitochondrial:cytoplasmic CoA gradient, also causing insufficient release of mitochondrial CoA as a response to cell stress and injury. Decreased palmitoylation capacity and decreased endocytosis and membrane remodelling are implicated in proven pathophysiological mechanisms in INAD and DMD. The described mechanism in INAD and DMD, may be considered a common mechanism of repair in case of cell stress and injury. Beside their role in INAD and DMD, they may therefore be implicated in other neurodegenerative diseases as well. Available research shows involvement of iPLA2β in other neurodegenerative diseases. We might be able to divide neurodegenerative diseases in "INAD-like disease-mechanism" or "DMD-like disease-mechanism", depending on decreased or increased iPLA2β activity. |
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| MeSH term(s) | Animals ; Disease Models, Animal ; Mitochondria ; Muscular Dystrophy, Duchenne ; Neuroaxonal Dystrophies ; Neurodegenerative Diseases |
| Language | English |
| Publishing date | 2020-01-23 |
| Publishing country | United States |
| Document type | Journal Article |
| ZDB-ID | 193145-3 |
| ISSN | 1532-2777 ; 0306-9877 |
| ISSN (online) | 1532-2777 |
| ISSN | 0306-9877 |
| DOI | 10.1016/j.mehy.2020.109589 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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