Glial A30P alpha-synuclein pathology segregates neurogenesis from anxiety-related behavior in conditional transgenic mice

Winner B, Marxreiter F, Ettle B, May VEL, Patrick C, Klucken J, Winkler J, Masliah E, Nuber S (2013)

Publication Language: English

Publication Status: Published

Publication Type: Journal article

Publication year: 2013

Journal

Neurobiology of Disease Elsevier

Publisher: ACADEMIC PRESS INC ELSEVIER SCIENCE

Book Volume: 59

Pages Range: 38-51

DOI: 10.1016/j.nbd.2013.07.004

Abstract

In Parkinson's disease (PD) patients, alpha-synuclein (alpha-syn) pathology advances in form of Lewy bodies and Lewy neurites throughout the brain. Clinically, PD is defined by motor symptoms that are predominantly attributed to the dopaminergic cell loss in the substantia nigra. However, motor deficits are frequently preceded by smell deficiency or neuropsychological symptoms, including increased anxiety and cognitive dysfunction. Accumulating evidence indicates that aggregation of alpha-syn impairs synaptic function and neurogenic capacity that may be associated with deficits in memory, learning and mood. Whether and how alpha-syn accumulation contributes to neuropathological events defining these earliest signs of PD is presently poorly understood.We used a tetracycline-suppressive (Let-off) transgenic mouse model that restricts overexpression of human A30P alpha-syn to neurons owing to usage of the neuron-specific CaMKIla promoter. Abnormal accumulation of A30P correlated with a decreased survival of newly generated neurons in the hippocampus and olfactory bulb. Furthermore, when A30P alpha-syn expression was suppressed, we observed reduction of the human protein in neuronal soma. However, residual dox resistant A30P alpha-syn was detected in glial cells within the hippocampal neurogenic niche, concomitant with the failure to fully restore hippocampal neurogenesis. This finding is indicative to a potential spread of pathology from neuron to glia. In addition, mice expressing A30P alpha-syn show increased anxiety-related behavior that was reversed after dox treatment. This implies that glial A30P alpha-synucleinopathy within the dentate gyrus is part of a process leading to impaired hippocampal neuroplasticity, which is, however, not a sole critical event for circuits implicated in anxiety-related behavior. (C) 2013 Elsevier Inc. All rights reserved.

Authors with CRIS profile

Beate Winner Medizinische Fakultät Franz Marxreiter Department of Molecular Neurology Benjamin Ettle Professur für Molekulare Neurologie Verena Elisabeth Luise May Department of Molecular Neurology Jochen Klucken Department of Molecular Neurology Jürgen Winkler Professur für Molekulare Neurologie

Involved external institutions

University of California, San Diego US United States (USA) (US)

How to cite

APA:

Winner, B., Marxreiter, F., Ettle, B., May, V.E.L., Patrick, C., Klucken, J.,... Nuber, S. (2013). Glial A30P alpha-synuclein pathology segregates neurogenesis from anxiety-related behavior in conditional transgenic mice. Neurobiology of Disease, 59, 38-51. https://doi.org/10.1016/j.nbd.2013.07.004

MLA:

Winner, Beate, et al. "Glial A30P alpha-synuclein pathology segregates neurogenesis from anxiety-related behavior in conditional transgenic mice." Neurobiology of Disease 59 (2013): 38-51.

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