Apoptosis in Parkinson's disease: is p53 the missing link between genetic and sporadic Parkinsonism?
Parkinson's disease (PD) is a major age-related neurodegenerative disorder characterized by a massive and specific loss of dopaminergic neurons of the substantia nigra pars compacta. The cellular alterations are clinically translated into an invalidating movement disability associated to three canonical symptoms that are bradykinesia, resting tremor and rigidity. The exact causes of this neuronal loss are unknown, but a network of evidences indicates a major contribution of orchestrated cell death processes, also known as apoptosis. Apoptotic cell death is a normal process, the alteration of which triggers several pathologies including cancer and neurodegenerative disorders. Exhaustive work has been done to delineate the cellular mechanisms responsible for the exacerbated cell death of dopaminergic neurons observed in PD. Overall, the oncogene p53 has been identified as a key effector protein. This review will focus on the clues linking p53 to the etiology of PD and the evidences that this protein may be at the center of multiple signaling cascades not only altered by mutations of various proteins responsible for familial cases of PD but also on more general sporadic cases of this devastating disease.
Institut de Pharmacologie Moléculaire et Cellulaire (IPMC) and Institut de NeuroMédecine Moléculaire (IN2M), UMR6097 CNRS/UNSA, team “Fondation pour la Recherche Médicale”,660 Route des Lucioles, 06560, Valbonne, France. acosta@ipmc.cnrs.fr
Cristine
C
Alves da Costa
Frédéric
F
Checler
D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D004195:Disease Models, Animal; D005808:Genes, Recessive; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D010300:Parkinson Disease / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
D047908:Intracellular Signaling Peptides and Proteins; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D015513:Oncogene Proteins; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases; D051844:alpha-Synuclein; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein; C495280:LRRK2 protein, human; C105131:PARK7 protein, human