Oxidative stress contributes differentially to the pathophysiology of Charcot-Marie-Tooth disease type 2K.
Experimental Neurology. 2020-01-01; 323: 113069
DOI: 10.1016/j.expneurol.2019.113069
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1. Exp Neurol. 2020 Jan;323:113069. doi: 10.1016/j.expneurol.2019.113069. Epub 2019
Oct 23.
Oxidative stress contributes differentially to the pathophysiology of
Charcot-Marie-Tooth disease type 2K.
Cassereau J(1), Chevrollier A(2), Codron P(3), Goizet C(4), Gueguen N(5), Verny
C(3), Reynier P(5), Bonneau D(5), Lenaers G(2), Procaccio V(5).
Author information:
(1)MitoLab, UMR CNRS 6015-INSERM 1083, MitoVasc Institute, University of Angers,
Angers, France; University Hospital of Angers, Department of Neurology, F-49100
Angers, France. Electronic address: .
(2)MitoLab, UMR CNRS 6015-INSERM 1083, MitoVasc Institute, University of Angers,
Angers, France.
(3)MitoLab, UMR CNRS 6015-INSERM 1083, MitoVasc Institute, University of Angers,
Angers, France; University Hospital of Angers, Department of Neurology, F-49100
Angers, France.
(4)Centre de Référence Neurogénétique, Service de Génétique, Hôpital Pellegrin,
University Hospital of Bordeaux and Laboratoire, MRGM, INSERM U1211, University
of Bordeaux, F-33000 Bordeaux, France.
(5)MitoLab, UMR CNRS 6015-INSERM 1083, MitoVasc Institute, University of Angers,
Angers, France; University Hospital of Angers, Department of Biochemistry and
Genetics, F-49100 Angers, France.
Charcot-Marie-Tooth (CMT) disease is a common inherited peripheral neuropathy.
The CMT2K axonal form is associated with GDAP1 dominant mutations, which
according to the affected domain cause a gradient of severity. Indeed, the
p.C240Y mutation, located within GDAP1 glutathione S-transferase (GST) domain and
associated to a mitochondrial complex I defect, is related to a faster disease
progression, compared to other mutations, such as the p.R120W located outside the
GST domain. Here, we analysed the pathophysiology of six CMT2K fibroblast cell
lines, carrying either the p.C240Y or p.R120W mutations. We show that complex I
deficiency leads to a redox potential alteration and a significant reduction of
sirtuin 1 (SIRT1) expression, a major deacetylase sensitive to the cellular redox
state, and NRF1 the downstream target of SIRT1. In addition, we disclosed that
the p.C240Y mutation is associated with a greater mitochondrial oxidative stress
than the p.R120W mutation. Moreover, complex I activity is further restored in
CMT2K mutant cell lines exposed to resveratrol. Together, these results suggest
that the reduction of oxidative stress may constitute a promising therapeutic
strategy for CMT2K.
Copyright © 2019 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.expneurol.2019.113069
PMID: 31655048 [Indexed for MEDLINE]