PMID- 32006920
OWN - NLM
STAT- MEDLINE
DCOM- 20210514
LR  - 20210514
IS  - 1532-2777 (Electronic)
IS  - 0306-9877 (Linking)
VI  - 137
DP  - 2020 Apr
TI  - INAD and Duchenne muscular dystrophy, two ends of the iPLA2beta spectrum.
PG  - 109589
LID - S0306-9877(19)31206-X [pii]
LID - 10.1016/j.mehy.2020.109589 [doi]
AB  - 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 iPLA2beta in INAD and 
      increased activity of iPLA2beta in DMD eventually lead to similar defects in the 
      response to cell stress and injury. According to this hypothesis, the depletion 
      of iPLA2beta 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 iPLA2beta 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 iPLA2beta 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 iPLA2beta 
      activity.
CI  - Copyright (c) 2020 Elsevier Ltd. All rights reserved.
FAU - Offringa-Hup, Annette
AU  - Offringa-Hup A
AD  - Clues2Cure, Dorpstraat 13, 6923AA Groessen, The Netherlands. Electronic address: 
      ak.offringa@clues2cure.org.
LA  - eng
PT  - Journal Article
DEP - 20200123
PL  - United States
TA  - Med Hypotheses
JT  - Medical hypotheses
JID - 7505668
SB  - IM
MH  - Animals
MH  - Disease Models, Animal
MH  - Mitochondria
MH  - *Muscular Dystrophy, Duchenne
MH  - *Neuroaxonal Dystrophies
MH  - *Neurodegenerative Diseases
COIS- Declaration of Competing Interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2020/02/02 06:00
MHDA- 2021/05/15 06:00
CRDT- 2020/02/02 06:00
PHST- 2019/10/24 00:00 [received]
PHST- 2019/12/21 00:00 [revised]
PHST- 2020/01/21 00:00 [accepted]
PHST- 2020/02/02 06:00 [pubmed]
PHST- 2021/05/15 06:00 [medline]
PHST- 2020/02/02 06:00 [entrez]
AID - S0306-9877(19)31206-X [pii]
AID - 10.1016/j.mehy.2020.109589 [doi]
PST - ppublish
SO  - Med Hypotheses. 2020 Apr;137:109589. doi: 10.1016/j.mehy.2020.109589. Epub 2020 
      Jan 23.