title: α-Synuclein induces alterations in adult neurogenesis in Parkinson disease models via p53-mediated repression of Notch1.
abstract: 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.
authors: Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, California 92093, USA. pdesplat@ucsd.edu
authors: Paula
authors: P
authors: Desplats
authors: Brian
authors: B
authors: Spencer
authors: Leslie
authors: L
authors: Crews
authors: Pruthul
authors: P
authors: Pathel
authors: Dinorah
authors: D
authors: Morvinski-Friedmann
authors: Kori
authors: K
authors: Kosberg
authors: Scott
authors: S
authors: Roberts
authors: Christina
authors: C
authors: Patrick
authors: Beate
authors: B
authors: Winner
authors: Juergen
authors: J
authors: Winkler
authors: Eliezer
authors: E
authors: Masliah
mesh_terms: D000818:Animals; D017209:Apoptosis; D019070:Cell Lineage; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D055495:Neurogenesis; D009474:Neurons / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: C497763:Notch1 protein, rat; D051881:Receptor, Notch1; D016159:Tumor Suppressor Protein p53; D051844:alpha-Synuclein