α-Synuclein induces alterations in adult neurogenesis in Parkinson disease models via p53-mediated repression of notch

Paula Desplats, Brian Spencer, Leslie Crews, Pruthul Pathel, Dinorah Morvinski-Friedmann, Kori Kosberg, Scott Roberts, Christina Patrick, Beate Winner, Juergen Winkler, Eliezer Masliah

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)31691-31702
Number of pages12
JournalJournal of Biological Chemistry
Volume287
Issue number38
DOIs
StatePublished - 14 Sep 2012
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Biochemistry
  • Cell Biology

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