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t h
E u r o S c i C o n C o n f e r e n c e o n
Neurology & Neurological
Disorders
Neurology 2018
J u l y 1 2 - 1 3 , 2 0 1 8
P a r i s , F r a n c e
Page 103
Journal of Neurology and Neuroscience
ISSN: 2171-6625
O
PA1 mutations cause Dominant Optic Atrophy (DOA), an incurable retinopathy with variable severity and which mechanisms
are still unknown. More than 20% of patients will endure a DOA plus syndrome with ataxia, deafness or Parkinsonism. We
evidenced oxidative stress in a mouse model of the pathology and aimed to identify the consequences of OPA1 inactivation on
redox homeostasis. We monitored the levels of mitochondrial respiration, reactive oxygen species (ROS), anti-oxidant defences
and cell death by biochemical and
in situ
approaches using in vitro and in vivo models of OPA1 related disorders. Increased ROS
levels were observed in cortices of the murine model OPA1
+/-
as well as in OPA1 down-regulated cortical neurons. This increase
is associated to a decline in mitochondrial respiration and an increase of antioxidant enzyme levels. Upon exogenous oxidative
stress OPA1-depleted neurons did not further up-regulated antioxidant defenses. Finally, low levels of antioxidant enzymes
were observed in fibroblasts from patients supporting their role as modifier factors. Our study shows: (i) the pro-oxidative state
induced by OPA1 loss can be considered as a pathological mechanism (ii) differences in antioxidant defences can contribute to
the variability in expressivity and (iii) antioxidant defences can be used as prognostic tools to gauge the severity and the evolution
of the disease. Furthermore, our discovery offers a way to model mathematically the dysfunctions of oxidative metabolism in
OPA1 gene related disorders. We will present the last results of our algorithm and wet laboratories experiments.
noelie.davezac@univ-tlse3.frImbalance of the redox state in OPA gene related
disorders: mathematical approaches to define
pathogenesis
Aurelie Millet
1
, Nadege Merabet
1
, Baptiste Alric
1
, Marlene
Daloyau
1
, Pascal Reynier
2
, Anne Galinier
3
, Anne Devin
4
, Bernd
Wissinger
5
, Pascale Belenguer
1
, Joel Bordeneuve-Guibe
6
and
Noelie Davezac
1
1
CBD-UMR 5547, Universite Toulouse III, Toulouse, France
2
U694 INSERM, CRNH Angers, UFR Sciences medicales, Angers
3
STROMALAB, CHU Toulouse-Hôpital de Rangueil, Toulouse, France
4
IBGC du CNRS, 1 rue Camille Saint Saëns, Bordeaux Cedex, France
5
University of Tübingen, Germany
6
ISAE SUPAERO, Universite de Toulouse, Toulouse, France
J Neurol Neurosci 2018, Volume: 9
DOI: 10.21767/2171-6625-C1-009