Changes in adult olfactory bulb neurogenesis in mice expressing the A30P mutant form of alpha-synuclein.
In familial and sporadic forms of Parkinson's 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.
Marxreiter
Franz
F
Department of Neurology, University of Regensburg, Universitätsstrasse 84, 93053 Regensburg, Germany.
Nuber
Silke
S
Kandasamy
Mahesh
M
Klucken
Jochen
J
Aigner
Robert
R
Burgmayer
Ralf
R
Couillard-Despres
Sebastien
S
Riess
Olaf
O
Winkler
Jürgen
J
Winner
Beate
B
D000409:Alanine / Q000235:genetics*; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D049109:Cell Proliferation; D000089622:Doublecortin Domain Proteins; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D055495:Neurogenesis / Q000235:genetics*; D009474:Neurons / Q000502:physiology; D009479:Neuropeptides / Q000378:metabolism; D009830:Olfactory Bulb / Q000166:cytology* / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011392:Proline / Q000235:genetics*; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism
D000089622:Doublecortin Domain Proteins; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D018809:Proliferating Cell Nuclear Antigen; D051844:alpha-Synuclein; D011392:Proline; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D000409:Alanine