title: Glial A30P alpha-synuclein pathology segregates neurogenesis from anxiety-related behavior in conditional transgenic mice.
abstract: In Parkinson's disease (PD) patients, alpha-synuclein (α-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 α-syn impairs synaptic function and neurogenic capacity that may be associated with deficits in memory, learning and mood. Whether and how α-syn accumulation contributes to neuropathological events defining these earliest signs of PD is presently poorly understood. We used a tetracycline-suppressive (tet-off) transgenic mouse model that restricts overexpression of human A30P α-syn to neurons owing to usage of the neuron-specific CaMKIIα promoter. Abnormal accumulation of A30P correlated with a decreased survival of newly generated neurons in the hippocampus and olfactory bulb. Furthermore, when A30P α-syn expression was suppressed, we observed reduction of the human protein in neuronal soma. However, residual dox resistant A30P α-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 α-syn show increased anxiety-related behavior that was reversed after dox treatment. This implies that glial A30P α-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.
authors.affiliation: Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Marxreiter
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ettle
authors.forename: Verena E L
authors.initials: VE
authors.lastname: May
authors.forename: Hakan
authors.initials: H
authors.lastname: Esmer
authors.forename: Christina
authors.initials: C
authors.lastname: Patrick
authors.forename: Christine Lund
authors.initials: CL
authors.lastname: Kragh
authors.forename: Jochen
authors.initials: J
authors.lastname: Klucken
authors.forename: Beate
authors.initials: B
authors.lastname: Winner
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
authors.forename: Jürgen
authors.initials: J
authors.lastname: Winkler
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Silke
authors.initials: S
authors.lastname: Nuber
mesh_terms: D000409:Alanine / Q000235:genetics*; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D002452:Cell Count; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D004318:Doxycycline / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics*; D009457:Neuroglia / Q000187:drug effects / Q000473:pathology*; D009479:Neuropeptides / Q000378:metabolism; D009830:Olfactory Bulb / Q000378:metabolism / Q000473:pathology; D011392:Proline / Q000235:genetics*; D051844:alpha-Synuclein / Q000235:genetics*
chemical_list: D000089622:Doublecortin Domain Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; C497604:SNCA protein, human; D051844:alpha-Synuclein; D011392:Proline; D004318:Doxycycline; D000409:Alanine
keywords: A30P alpha-synuclein; Conditional; Gliosis; Parkinson's disease; Propagation; S100B; Transgenic