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

João Paulo L. Daher, Mingyao Ying, Rebecca Banerjee, Rebecca S. McDonald, Myriam Dumas Hahn, Lichuan Yang, M. Flint Beal, Bobby Thomas, Valina L. Dawson, Ted M. Dawson, Darren J. Moore

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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.

Original languageEnglish (US)
Article number34
JournalMolecular Neurodegeneration
Volume4
Issue number1
DOIs
StatePublished - Aug 27 2009
Externally publishedYes

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Synucleins
Corpus Striatum
Dopaminergic Neurons
Transgenic Mice
Dopamine
Parkinson Disease
Substantia Nigra
Lewy Bodies
Cytomegalovirus Infections
Missense Mutation

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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Conditional transgenic mice expressing C-terminally truncated human α-synuclein (αSyn119) exhibit reduced striatal dopamine without loss of nigrostriatal pathway dopaminergic neurons. / Daher, João Paulo L.; Ying, Mingyao; Banerjee, Rebecca; McDonald, Rebecca S.; Hahn, Myriam Dumas; Yang, Lichuan; Beal, M. Flint; Thomas, Bobby; Dawson, Valina L.; Dawson, Ted M.; Moore, Darren J.

In: Molecular Neurodegeneration, Vol. 4, No. 1, 34, 27.08.2009.

Research output: Contribution to journalArticle

Daher, João Paulo L. ; Ying, Mingyao ; Banerjee, Rebecca ; McDonald, Rebecca S. ; Hahn, Myriam Dumas ; Yang, Lichuan ; Beal, M. Flint ; Thomas, Bobby ; Dawson, Valina L. ; Dawson, Ted M. ; Moore, Darren J. / Conditional transgenic mice expressing C-terminally truncated human α-synuclein (αSyn119) exhibit reduced striatal dopamine without loss of nigrostriatal pathway dopaminergic neurons. In: Molecular Neurodegeneration. 2009 ; Vol. 4, No. 1.
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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.",
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AU - Ying, Mingyao

AU - Banerjee, Rebecca

AU - McDonald, Rebecca S.

AU - Hahn, Myriam Dumas

AU - Yang, Lichuan

AU - Beal, M. Flint

AU - Thomas, Bobby

AU - Dawson, Valina L.

AU - Dawson, Ted M.

AU - Moore, Darren J.

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