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Forschungsdatenbank PMU-SQQUID

Changes in adult olfactory bulb neurogenesis in mice expressing the A30P mutant form of alpha-synuclein.
Marxreiter, F; Nuber, S; Kandasamy, M; Klucken, J; Aigner, R; Burgmayer, R; Couillard-Despres, S; Riess, O; Winkler, J; Winner, B;
EUR J NEUROSCI. 2009; 29(5): 87-90.
Originalarbeiten (Zeitschrift)

PMU-Autor/inn/en

Couillard-Després Sébastien

Abstract

In familial and sporadic forms of Parkinsonxxxs disease (PD), alpha-synuclein pathology is present in the brain stem nuclei and olfactory bulb (OB) long before Lewy bodies are detected in the substantia nigra. The OB is an active region of adult neurogenesis, where newly generated neurons physiologically integrate. While accumulation of wild-type alpha-synuclein is one of the pathogenic hallmarks of non-genetic forms of PD, the A30P alpha-synuclein mutation results in an earlier disease onset and a severe clinical phenotype. Here, we study the regulation of adult neurogenesis in the subventricular zone (SVZ)/OB system in a tetracycline-suppressive (tet-off) transgenic model of synucleinopathies, expressing human mutant A30P alpha-synuclein under the control of the calcium/calmodulin-dependent protein kinase II alpha (CaMK) promoter. In A30P transgenic mice alpha-synuclein was abundant at the site of integration in the glomerular cell layer of the OB. Without changes in proliferation in the SVZ, significantly fewer newly generated neurons were observed in the OB granule cell and glomerular layers of A30P transgenic mice than in controls, most probably due to increased cell death. By tetracycline-dependent abrogation of A30P alpha-synuclein expression, OB neurogenesis and programmed cell death was restored to control levels. Our results indicate that, using A30P conditional (tet-off) mice, A30P alpha-synuclein has a negative impact on olfactory neurogenesis and suppression of A30P alpha-synuclein enhances survival of newly generated neurons. This finding suggests that interfering with alpha-synuclein pathology can rescue newly generated neurons, possibly leading to new targets for therapeutic interventions in synucleinopathies.


Useful keywords (using NLM MeSH Indexing)

Alanine/genetics*

Animals

Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism

Cell Death/genetics

Cell Proliferation

Humans

Mice

Mice, Inbred C57BL

Mice, Transgenic

Microtubule-Associated Proteins/metabolism

Mutation/genetics*

Neurogenesis/genetics*

Neurons/physiology

Neuropeptides/metabolism

Olfactory Bulb/cytology*

Olfactory Bulb/metabolism

Proliferating Cell Nuclear Antigen/metabolism

Proline/genetics*

alpha-Synuclein/genetics*

alpha-Synuclein/metabolism


Find related publications in this database (Keywords)

adult neurogenesis
neural progenitor cells
Parkinson disease
subventricular zone
synucleinopathies