α-Synuclein induces alterations in adult neurogenesis in Parkinson disease models via p53-mediated repression of Notch1.

Desplats P, Spencer B, Crews L, Pathel P, Morvinski-Friedmann D, Kosberg K, Roberts S, Patrick C, Winner B, Winkler J, Masliah E (2012)

Publication Status: Published

Publication Type: Journal article

Publication year: 2012

Journal

Journal of Biological Chemistry American Society for Biochemistry and Molecular Biology

Book Volume: 287

Pages Range: 31691-702

Journal Issue: 38

DOI: 10.1074/jbc.M112.354522

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 with CRIS profile

Beate Winner Professur für Stammzell-Modelle seltener neuraler Erkrankungen Jürgen Winkler Professur für Molekulare Neurologie

Involved external institutions

Mississippi State University for Agriculture and Applied Science US United States (USA) (US) University of California, San Diego US United States (USA) (US)

How to cite

APA:

Desplats, P., Spencer, B., Crews, L., Pathel, P., Morvinski-Friedmann, D., Kosberg, K.,... Masliah, E. (2012). α-Synuclein induces alterations in adult neurogenesis in Parkinson disease models via p53-mediated repression of Notch1. Journal of Biological Chemistry, 287(38), 31691-702. https://doi.org/10.1074/jbc.M112.354522

MLA:

Desplats, Paula, et al. "α-Synuclein induces alterations in adult neurogenesis in Parkinson disease models via p53-mediated repression of Notch1." Journal of Biological Chemistry 287.38 (2012): 31691-702.

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