α-Synuclein Induces Alterations in Adult Neurogenesis in Parkinson Disease Models via p53-mediated Repression of Notch1

• Published in: The Journal of biological chemistry 2012-09, Vol.287 (38), p.31691-31702
• Main Authors: Desplats, Paula, Spencer, Brian, Crews, Leslie, Pathel, Pruthul, Morvinski-Friedmann, Dinorah, Kosberg, Kori, Roberts, Scott, Patrick, Christina, Winner, Beate, Winkler, Juergen, Masliah, Eliezer
• Format: Article
• Language: English
• Subjects: Adult Neurogenesis; Alpha-Synuclein; alpha-Synuclein - metabolism; Animals; Apoptosis; Cell Lineage; Disease Models, Animal; Gene Expression Regulation; Hippocampus - metabolism; Lentivirus - genetics; Molecular Bases of Disease; Neurogenesis; Neurons - metabolism; Notch; p53; Parkinson Disease; Parkinson Disease - metabolism; Promoter Regions, Genetic; Rats; Receptor, Notch1 - metabolism; Signal Transduction; Transcription Regulation; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.354522

Parkinson disease is characterized by the loss of dopaminergic neurons mainly in the substantia nigra. Accumulation of α-synuclein and cell loss has been also reported in many other brain regions including the hippocampus, where it might impair adult neurogenesis, contributing to nonmotor symptoms. However, the molecular mechanisms of these alterations are still unknown. In this report we show that α-synuclein-accumulating adult rat hippocampus neural progenitors present aberrant neuronal differentiation, with reduction of Notch1 expression and downstream signaling targets. We characterized a Notch1 proximal promoter that contains p53 canonical response elements. In vivo binding of p53 represses the transcription of Notch1 in neurons. Moreover, we demonstrated that α-synuclein directly binds to the DNA at Notch1 promoter vicinity and also interacts with p53 protein, facilitating or increasing Notch1 signaling repression, which interferes with maturation and survival of neural progenitors cells. This study provides a molecular basis for α-synuclein-mediated disruption of adult neurogenesis in Parkinson disease. Background: α-Synuclein accumulation alters adult neurogenesis by down-regulation of Notch1. Results: p53 is a negative regulator of Notch1 transcription, and interaction with α-synuclein further represses Notch1 expression. Conclusion: p53 mediates the α synuclein-induced alterations of adult neurogenesis. Significance: This might be the first link between p53 effects and aberrant neurogenesis in synucleopathies.