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A progressive dopaminergic phenotype associated with neurotoxic conversion of ?-synuclein in BAC-transgenic rats.

ABSTRACT: Conversion of soluble ?-synuclein into insoluble and fibrillar inclusions is a hallmark of Parkinson's disease and other synucleinopathies. Accumulating evidence points towards a relationship between its generation at nerve terminals and structural synaptic pathology. Little is known about the pathogenic impact of ?-synuclein conversion and deposition at nigrostriatal dopaminergic synapses in transgenic mice, mainly owing to expression limitations of the ?-synuclein construct. Here, we explore whether both the rat as a model and expression of the bacterial artificial chromosome construct consisting of human full-length wild-type ?-synuclein could exert dopaminergic neuropathological effects. We found that the human promoter induced a pan-neuronal expression, matching the rodent ?-synuclein expression pattern, however, with prominent C-terminally truncated fragments. Ageing promoted conversion of both full-length and C-terminally truncated ?-synuclein species into insolube and proteinase K-resistant fibres, with strongest accumulation in the striatum, resembling biochemical changes seen in human Parkinson's disease. Transgenic rats develop early changes in novelty-seeking, avoidance and smell before the progressive motor deficit. Importantly, the observed pathological changes were associated with severe loss of the dopaminergic integrity, thus resembling more closely the human pathology.

SUBMITTER: Nuber S

PROVIDER: S-EPMC3572936 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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A progressive dopaminergic phenotype associated with neurotoxic conversion of α-synuclein in BAC-transgenic rats.

Nuber Silke S Harmuth Florian F Kohl Zacharias Z Adame Anthony A Trejo Margaritha M Schönig Kai K Zimmermann Frank F Bauer Claudia C Casadei Nicolas N Giel Christiane C Calaminus Carsten C Pichler Bernd J BJ Jensen Poul H PH Müller Christian P CP Amato Davide D Kornhuber Johannes J Teismann Peter P Yamakado Hodaka H Takahashi Ryosuke R Winkler Juergen J Masliah Eliezer E Riess Olaf O

Brain : a journal of neurology 20130201 Pt 2

Conversion of soluble α-synuclein into insoluble and fibrillar inclusions is a hallmark of Parkinson's disease and other synucleinopathies. Accumulating evidence points towards a relationship between its generation at nerve terminals and structural synaptic pathology. Little is known about the pathogenic impact of α-synuclein conversion and deposition at nigrostriatal dopaminergic synapses in transgenic mice, mainly owing to expression limitations of the α-synuclein construct. Here, we explore w ...[more]

PMID: 23413261

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Project description:Parkinson's disease (PD) is a multisystem disorder, involving several monoaminergic neurotransmitter systems resulting in a broad range of motor and non-motor symptoms. Pathological hallmarks of PD are the loss of dopaminergic neurons and the accumulation of alpha-synuclein, however also being present in the serotonergic raphe nuclei early in the disease course. The dysfunction of the serotonergic system projecting to the hippocampus may contribute to early non-motor symptoms such as anxiety and depression. The adult hippocampal dentate gyrus (DG), a unique niche of the forebrain continuously generating new neurons, may particularly present enhanced susceptibility towards accumulating alpha-synuclein levels. The underlying molecular mechanisms in the context of neuronal maturation and survival of new-born neurons are yet not well understood. To characterize the effects of overexpression of human full-length alpha-synuclein on hippocampal cellular and synaptic plasticity, we used a recently generated BAC alpha-synuclein transgenic rat model showing important features of PD such as widespread and progressive alpha-synuclein aggregation pathology, dopamine loss and age-dependent motor decline. At the age of four months, thus prior to the occurrence of the motor phenotype, we observed a profoundly impaired dendritogenesis of neuroblasts in the hippocampal DG resulting in severely reduced survival of adult new-born neurons. Diminished neurogenesis concurred with a serotonergic deficit in the hippocampus as defined by reduced levels of serotonin (5-HT) 1B receptor, decreased 5-HT neurotransmitter levels, and a loss of serotonergic nerve terminals innervating the DG/CA3 subfield, while the number of serotonergic neurons in the raphe nuclei remained unchanged. Moreover, alpha-synuclein overexpression reduced proteins involved in vesicle release, in particular synapsin-1 and Rab3 interacting molecule (RIM3), in conjunction with an altered ultrastructural architecture of hippocampal synapses. Importantly, BAC alpha-synuclein rats showed an early anxiety-like phenotype consisting of reduced exploratory behavior and feeding. Taken together, these findings imply that accumulating alpha-synuclein severely affects hippocampal neurogenesis paralleled by impaired 5-HT neurotransmission prior to the onset of aggregation pathology and overt motor deficits in this transgenic rat model of PD.

Dataset Information

A progressive dopaminergic phenotype associated with neurotoxic conversion of ?-synuclein in BAC-transgenic rats.

Publications

A progressive dopaminergic phenotype associated with neurotoxic conversion of α-synuclein in BAC-transgenic rats.

Similar Datasets

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