Motor dysfunction and gliosis with preserved dopaminergic markers in human α-synuclein A30P transgenic mice

Teresa Gomez-Isla, Michael C. Irizarry, Ami Mariash, Bonnie Cheung, Oscar Soto, Stefanie Schrump, Jesse Sondel, Linda Kotilinek, John Day, Michael A. Schwarzschild, Jang Ho J. Cha, Kathy Newell, David W. Miller, Kenji Uéda, Anne B. Young, Bradley T. Hyman, Karen H. Ashe

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Abstract

α-Synuclein is a major component of Lewy bodies (LBs) in the substantia nigra and cortex in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), and in glial inclusions in multiple systems atrophy (MSA). Mutations in α-synuclein have been associated with autosomal dominant forms of PD. We investigated the clinical and neuropathological effects of overexpression of human α-synuclein, α-synuclein A30P, and α-synuclein A53T under the control of the hamster prion protein (PrP) promoter; 5-15× endogenous levels of protein expression were achieved with widespread neuronal, including nigral, transgene expression. High expression of α-synuclein A30P in the Tg5093 line was associated with a progressive motor disorder with rigidity, dystonia, gait impairment, and tremor. Histological analysis of this line showed aberrant expression of the protein in cell soma and progressive CNS gliosis, but no discrete Lewy body-like α-synuclein inclusions could be identified. Biochemical analysis demonstrated α-synuclein fragmentation. Despite strong expression of the transgene in the nigra, there was no specific deterioration of the nigrostriatal dopaminergic system as assessed by quantitation of nigral tyrosine hydroxylase (TH) containing neurons, striatal TH immunoreactivity, dopamine levels, or dopamine receptor number and function. Lower expressing lines had no specific behavioral or histopathological phenotype. Thus, high expression of mutant human α-synuclein resulted in a progressive motor and widespread CNS gliotic phenotype independent of dopaminergic dysfunction in the Tg5093 line.

Original languageEnglish (US)
Pages (from-to)245-258
Number of pages14
JournalNeurobiology of Aging
Volume24
Issue number2
DOIs
StatePublished - Mar 1 2003

Fingerprint

Synucleins
Gliosis
Transgenic Mice
Substantia Nigra
Lewy Bodies
Tyrosine 3-Monooxygenase
Transgenes
Multiple System Atrophy
Phenotype
Corpus Striatum
Lewy Body Disease
Dystonia
Dopamine Receptors
Carisoprodol
Tremor
Gait
Neuroglia
Cricetinae
Parkinson Disease
Dopamine

Keywords

  • Dopamine
  • Lewy body
  • Parkinson's disease
  • Substantia nigra
  • Synuclein
  • Transgenic mice
  • Tyrosine hydroxylase

Cite this

Motor dysfunction and gliosis with preserved dopaminergic markers in human α-synuclein A30P transgenic mice. / Gomez-Isla, Teresa; Irizarry, Michael C.; Mariash, Ami; Cheung, Bonnie; Soto, Oscar; Schrump, Stefanie; Sondel, Jesse; Kotilinek, Linda; Day, John; Schwarzschild, Michael A.; Cha, Jang Ho J.; Newell, Kathy; Miller, David W.; Uéda, Kenji; Young, Anne B.; Hyman, Bradley T.; Ashe, Karen H.

In: Neurobiology of Aging, Vol. 24, No. 2, 01.03.2003, p. 245-258.

Research output: Contribution to journalArticle

Gomez-Isla, T, Irizarry, MC, Mariash, A, Cheung, B, Soto, O, Schrump, S, Sondel, J, Kotilinek, L, Day, J, Schwarzschild, MA, Cha, JHJ, Newell, K, Miller, DW, Uéda, K, Young, AB, Hyman, BT & Ashe, KH 2003, 'Motor dysfunction and gliosis with preserved dopaminergic markers in human α-synuclein A30P transgenic mice', Neurobiology of Aging, vol. 24, no. 2, pp. 245-258. https://doi.org/10.1016/S0197-4580(02)00091-X
Gomez-Isla, Teresa ; Irizarry, Michael C. ; Mariash, Ami ; Cheung, Bonnie ; Soto, Oscar ; Schrump, Stefanie ; Sondel, Jesse ; Kotilinek, Linda ; Day, John ; Schwarzschild, Michael A. ; Cha, Jang Ho J. ; Newell, Kathy ; Miller, David W. ; Uéda, Kenji ; Young, Anne B. ; Hyman, Bradley T. ; Ashe, Karen H. / Motor dysfunction and gliosis with preserved dopaminergic markers in human α-synuclein A30P transgenic mice. In: Neurobiology of Aging. 2003 ; Vol. 24, No. 2. pp. 245-258.
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abstract = "α-Synuclein is a major component of Lewy bodies (LBs) in the substantia nigra and cortex in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), and in glial inclusions in multiple systems atrophy (MSA). Mutations in α-synuclein have been associated with autosomal dominant forms of PD. We investigated the clinical and neuropathological effects of overexpression of human α-synuclein, α-synuclein A30P, and α-synuclein A53T under the control of the hamster prion protein (PrP) promoter; 5-15× endogenous levels of protein expression were achieved with widespread neuronal, including nigral, transgene expression. High expression of α-synuclein A30P in the Tg5093 line was associated with a progressive motor disorder with rigidity, dystonia, gait impairment, and tremor. Histological analysis of this line showed aberrant expression of the protein in cell soma and progressive CNS gliosis, but no discrete Lewy body-like α-synuclein inclusions could be identified. Biochemical analysis demonstrated α-synuclein fragmentation. Despite strong expression of the transgene in the nigra, there was no specific deterioration of the nigrostriatal dopaminergic system as assessed by quantitation of nigral tyrosine hydroxylase (TH) containing neurons, striatal TH immunoreactivity, dopamine levels, or dopamine receptor number and function. Lower expressing lines had no specific behavioral or histopathological phenotype. Thus, high expression of mutant human α-synuclein resulted in a progressive motor and widespread CNS gliotic phenotype independent of dopaminergic dysfunction in the Tg5093 line.",
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AU - Schrump, Stefanie

AU - Sondel, Jesse

AU - Kotilinek, Linda

AU - Day, John

AU - Schwarzschild, Michael A.

AU - Cha, Jang Ho J.

AU - Newell, Kathy

AU - Miller, David W.

AU - Uéda, Kenji

AU - Young, Anne B.

AU - Hyman, Bradley T.

AU - Ashe, Karen H.

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N2 - α-Synuclein is a major component of Lewy bodies (LBs) in the substantia nigra and cortex in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), and in glial inclusions in multiple systems atrophy (MSA). Mutations in α-synuclein have been associated with autosomal dominant forms of PD. We investigated the clinical and neuropathological effects of overexpression of human α-synuclein, α-synuclein A30P, and α-synuclein A53T under the control of the hamster prion protein (PrP) promoter; 5-15× endogenous levels of protein expression were achieved with widespread neuronal, including nigral, transgene expression. High expression of α-synuclein A30P in the Tg5093 line was associated with a progressive motor disorder with rigidity, dystonia, gait impairment, and tremor. Histological analysis of this line showed aberrant expression of the protein in cell soma and progressive CNS gliosis, but no discrete Lewy body-like α-synuclein inclusions could be identified. Biochemical analysis demonstrated α-synuclein fragmentation. Despite strong expression of the transgene in the nigra, there was no specific deterioration of the nigrostriatal dopaminergic system as assessed by quantitation of nigral tyrosine hydroxylase (TH) containing neurons, striatal TH immunoreactivity, dopamine levels, or dopamine receptor number and function. Lower expressing lines had no specific behavioral or histopathological phenotype. Thus, high expression of mutant human α-synuclein resulted in a progressive motor and widespread CNS gliotic phenotype independent of dopaminergic dysfunction in the Tg5093 line.

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