NDLI: Conditional transgenic mice expressing C-terminally truncated human α-synuclein (αSyn119) exhibit reduced striatal dopamine without loss of nigrostriatal pathway dopaminergic neurons

Content Provider	Springer Nature : BioMed Central
Author	Daher, João Paulo L Ying, Mingyao Banerjee, Rebecca McDonald, Rebecca S Hahn, Myriam Dumas Yang, Lichuan Flint Beal, M Thomas, Bobby Dawson, Valina L Dawson, Ted M Moore, Darren J
Abstract	Background Missense mutations and multiplications of the α-synuclein gene cause autosomal dominant familial Parkinson's disease (PD). α-Synuclein protein is also a major component of Lewy bodies, the hallmark pathological inclusions of PD. Therefore, α-synuclein plays an important role in the pathogenesis of familial and sporadic PD. To model α-synuclein-linked disease in vivo, transgenic mouse models have been developed that express wild-type or mutant human α-synuclein from a variety of neuronal-selective heterologous promoter elements. These models exhibit a variety of behavioral and neuropathological features resembling some aspects of PD. However, an important deficiency of these models is the observed lack of robust or progressive nigrostriatal dopaminergic neuronal degeneration that is characteristic of PD. Results We have developed conditional α-synuclein transgenic mice that can express A53T, E46K or C-terminally truncated (1–119) human α-synuclein pathological variants from the endogenous murine ROSA26 promoter in a Cre recombinase-dependent manner. Using these mice, we have evaluated the expression of these α-synuclein variants on the integrity and viability of nigral dopaminergic neurons with age. Expression of A53T α-synuclein or truncated αSyn119 selectively in nigrostriatal pathway dopaminergic neurons for up to 12 months fails to precipitate dopaminergic neuronal loss in these mice. However, αSyn119 expression in nigral dopaminergic neurons for up to 12 months causes a marked reduction in the levels of striatal dopamine and its metabolites together with other subtle neurochemical alterations. Conclusion We have developed and evaluated novel conditional α-synuclein transgenic mice with transgene expression directed selectively to nigrostriatal dopaminergic neurons as a potential new mouse model of PD. Our data support the pathophysiological relevance of C-terminally truncated α-synuclein species in vivo. The expression of αSyn119 in the mouse nigrostriatal dopaminergic pathway may provide a useful model of striatal dopamine depletion and could potentially provide a presymptomatic model of PD perhaps representative of the earliest derangements in dopaminergic neuronal function observed prior to neuronal loss. These conditional α-synuclein transgenic mice provide novel tools for evaluating and dissecting the age-related effects of α-synuclein pathological variants on the function of the nigrostriatal dopaminergic pathway or other specific neuronal populations.
Related Links	https://molecularneurodegeneration.biomedcentral.com/counter/pdf/10.1186/1750-1326-4-34.pdf
Ending Page	14
Page Count	14
Starting Page	1
File Format	HTM / HTML
ISSN	17501326
DOI	10.1186/1750-1326-4-34
Journal	Molecular Neurodegeneration
Issue Number	1
Volume Number	4
Language	English
Publisher	BioMed Central
Publisher Date	2009-07-24
Access Restriction	Open
Subject Keyword	Neurosciences Neurology Molecular Medicine Dementia With Lewy Body Nigral Dopaminergic Neuron Nigrostriatal Dopaminergic Pathway Conditional Transgenic Mouse Nigrostriatal Pathway Dopaminergic Neuron
Content Type	Text
Resource Type	Article
Subject	Neurology (clinical) Molecular Biology Cellular and Molecular Neuroscience
Journal Impact Factor	15.1/2023
5-Year Journal Impact Factor	16.8/2023

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