Neurodegenerative disorders (ND) include a wide spectrum of diseases characterized by progressive neuronal dysfunctions or degeneration. With an estimated cost of 135 billion € in 2010 in the European Union (Olesen et al., 2012Olesen J., Gustavsson A., Svensson M., Wittchen H.-U., Jönsson B.on behalf of the CDBE2010 study group, and the European Brain Council The economic cost of brain disorders in Europe Eur J Neurol 2012 ;  19 : 155-162 [cross-ref]

Cliquez ici pour aller à la section Références), 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 (α-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.

La maladie de Parkinson, d’étiologie inconnue, est associée à une dégénérescence des neurones dopaminergiques de la voie nigro-striée. L’élucidation des mécanismes physiopathologiques de la maladie constituerait une étape clé dans la mise au point de thérapies permettant de ralentir la progression de la maladie. Ces mécanismes sont, à ce jour, inconnus. Toutefois, un faisceau convergent d’observations permet de soupçonner que des défauts mitochondriaux constituent un événement précoce de la dégénérescence dopaminergique. Ces soupçons se basent sur l’étude des cas sporadiques ainsi que sur celle des modèles d’intoxication et des modèles génétiques de la maladie. Dans cette revue, nous proposerons une analyse critique des éléments incriminant des dysfonctions mitochondriales dans ces différents modèles. Nous discuterons de leur pertinence vis-à-vis des formes sporadiques de la maladie ainsi que des perspectives thérapeutiques ouvertes.