title: A novel α-synuclein-GFP mouse model displays progressive motor impairment, olfactory dysfunction and accumulation of α-synuclein-GFP.
abstract: Compelling evidence suggests that accumulation and aggregation of alpha-synuclein (α-syn) contribute to the pathogenesis of Parkinson's disease (PD). Here, we describe a novel Bacterial Artificial Chromosome (BAC) transgenic model, in which we have expressed wild-type human α-syn fused to green fluorescent protein (GFP), under control of the mouse α-syn promoter. We observed a widespread and high expression of α-syn-GFP in multiple brain regions, including the dopaminergic neurons of the substantia nigra pars compacta (SNpc) and the ventral tegmental area, the olfactory bulb as well as in neocortical neurons. With increasing age, transgenic mice exhibited reductions in amphetamine-induced locomotor activity in the open field, impaired rotarod performance and a reduced striatal dopamine release, as measured by amperometry. In addition, they progressively developed deficits in an odor discrimination test. Western blot analysis revealed that α-syn-GFP and phospho-α-syn levels increased in multiple brain regions, as the mice grew older. Further, we observed, by immunohistochemical staining for phospho-α-syn and in vivo by two-photon microscopy, the formation of α-syn aggregates as the mice aged. The latter illustrates that the model can be used to track α-syn aggregation in vivo. In summary, this novel BAC α-syn-GFP model mimics a unique set of aspects of PD progression combined with the possibility of tracking α-syn aggregation in neocortex of living mice. Therefore, this α-syn-GFP-mouse model can provide a powerful tool that will facilitate the study of α-syn biology and its involvement in PD pathogenesis.
authors: Neural Plasticity and Repair Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, BMC A10, 221 84 Lund, Sweden. Christian.hansen@med.lu.se
authors: Christian
authors: C
authors: Hansen
authors: Tomas
authors: T
authors: Björklund
authors: Geraldine H
authors: GH
authors: Petit
authors: Martin
authors: M
authors: Lundblad
authors: Reena Prity
authors: RP
authors: Murmu
authors: Patrik
authors: P
authors: Brundin
authors: Jia-Yi
authors: JY
authors: Li
mesh_terms: D000375:Aging / Q000378:metabolism / Q000523:psychology; D000661:Amphetamine; D000818:Animals; D004192:Discrimination, Psychological / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents; D059290:Dopaminergic Neurons / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008124:Locomotion / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009069:Movement Disorders / Q000235:genetics* / Q000503:physiopathology* / Q000523:psychology; D019579:Neocortex / Q000473:pathology; D009422:Nervous System Diseases / Q000235:genetics* / Q000503:physiopathology* / Q000523:psychology; D000857:Olfaction Disorders / Q000235:genetics* / Q000503:physiopathology* / Q000523:psychology; D012903:Smell / Q000187:drug effects; D013378:Substantia Nigra / Q000473:pathology; D017557:Ventral Tegmental Area / Q000473:pathology; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*
chemical_list: D015259:Dopamine Agents; D051844:alpha-Synuclein; D049452:Green Fluorescent Proteins; D000661:Amphetamine; D004298:Dopamine