Article

Neurodegenerative disorders (ND) include a wide spectrum of diseases
characterized by progressive neuronal dysfunctions or degeneration. With an
estimated cost of 135 billion euro in 2010 in the European Union (Olesen et al.,
2012), they put an enormous economic as well as social burden on modern
societies. Hence, they have been the subject of a huge amount of research for the
last fifty years. For many of these diseases, our understanding of their profound
causes is incomplete and this hinders the discovery of efficient therapies. ND
form a highly heterogeneous group of diseases affecting various neuronal
subpopulations reflecting different origins and different pathological
mechanisms. However, some common themes in the physiopathology of these disorders
are emerging. There is growing evidence that mitochondrial dysfunctions play a
pivotal role at some point in the course of neurodegeneration. In some cases
(e.g. Alzheimer's disease, amyotrophic lateral sclerosis), impairment of
mitochondrial functions probably occurs late in the course of the disease. In a
subset of ND, current evidence suggests that mitochondrial dysfunctions play a
more seminal role in neuronal demise. Parkinson's disease (PD) presents one of
the strongest cases based in part on post-mortem studies that have shown
mitochondrial impairment (e.g. reduced complex I activity) and oxidative damage
in idiopathic PD brains. The occurrence of PD is largely sporadic, but clinical
syndromes resembling sporadic PD have been linked to specific environmental
insults or to mutations in at least 5 distinct genes (alpha-synuclein, parkin,
DJ-1, PINK1 and LRRK2). It is postulated that the elucidation of the pathogenic
mechanisms underlying the selective dopaminergic degeneration in familial and
environmental Parkinsonism should provide important clues to the pathogenic
mechanisms responsible for idiopathic PD. Hence, numerous cellular and animal
models of the disease have been generated that mimic these environmental or
genetic insults. The study of these models has yielded valuable information
regarding the pathogenic mechanisms underlying dopaminergic degeneration in PD,
many of which point towards an involvement of mitochondrial dysfunction. In this
short review we will analyze critically the experimental evidence for the
mitochondrial origin of PD and evaluate its relevance for our general
understanding of the disease.
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Langue : ANGLAIS