Analysis of cellular, transgenic and human models of Huntington's disease reveals tyrosine hydroxylase alterations and substantia nigra neuropathology

George J. Yohrling IV; George C.T. Jiang; Molly M. DeJohn; David W. Miller; Anne B. Young; Kent E. Vrana; Jang Ho J. Cha

doi:10.1016/j.molbrainres.2003.08.009

Analysis of cellular, transgenic and human models of Huntington's disease reveals tyrosine hydroxylase alterations and substantia nigra neuropathology

George J. Yohrling IV, George C.T. Jiang, Molly M. DeJohn, David W. Miller, Anne B. Young, Kent E. Vrana, Jang Ho J. Cha

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Abstract

Huntington's disease (HD) is a progressive, autosomal dominant neurodegenerative disorder that is pathologically characterized by a striatal-specific degeneration. Aberrant dopamine neurotransmission has been proposed as a mechanism underlying the movement disorder of HD. We report that the enzymatic activity of tyrosine hydroxylase (TH), the rate-limiting enzyme for dopamine biosynthesis, is decreased in a transgenic mouse model of HD. In addition, mutant huntingtin was found to disrupt transcription of TH and dopamine β-hydroxylase (DβH) promoter reporter constructs. In situ hybridization revealed extensive loss of TH mRNA and decreased dopaminergic cell size in human HD substantia nigra. TH-immunoreactive protein was reduced in human grade 4 HD substantia nigra by 32% compared to age-matched controls. These findings implicate abnormalities in dopamine neurotransmission in HD and may provide new insights into targets for pharmacotherapy.

Original language	English (US)
Pages (from-to)	28-36
Number of pages	9
Journal	Molecular Brain Research
Volume	119
Issue number	1
DOIs	https://doi.org/10.1016/j.molbrainres.2003.08.009
State	Published - Nov 6 2003

All Science Journal Classification (ASJC) codes

Molecular Biology
Cellular and Molecular Neuroscience

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.molbrainres.2003.08.009

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title = "Analysis of cellular, transgenic and human models of Huntington's disease reveals tyrosine hydroxylase alterations and substantia nigra neuropathology",

abstract = "Huntington's disease (HD) is a progressive, autosomal dominant neurodegenerative disorder that is pathologically characterized by a striatal-specific degeneration. Aberrant dopamine neurotransmission has been proposed as a mechanism underlying the movement disorder of HD. We report that the enzymatic activity of tyrosine hydroxylase (TH), the rate-limiting enzyme for dopamine biosynthesis, is decreased in a transgenic mouse model of HD. In addition, mutant huntingtin was found to disrupt transcription of TH and dopamine β-hydroxylase (DβH) promoter reporter constructs. In situ hybridization revealed extensive loss of TH mRNA and decreased dopaminergic cell size in human HD substantia nigra. TH-immunoreactive protein was reduced in human grade 4 HD substantia nigra by 32% compared to age-matched controls. These findings implicate abnormalities in dopamine neurotransmission in HD and may provide new insights into targets for pharmacotherapy.",

author = "{Yohrling IV}, {George J.} and Jiang, {George C.T.} and DeJohn, {Molly M.} and Miller, {David W.} and Young, {Anne B.} and Vrana, {Kent E.} and Cha, {Jang Ho J.}",

note = "Funding Information: We would like to thank the Harvard Brain Tissue Resource Center for the human brain samples. They are supported in part by PHS grant MH/NS-31862. We would also like to thank Dr. Gillian Bates (King's College, London, UK) for generously supplying us with the R6/2 mice to perform these studies, Dr. Kwang-Soo Kim (McLean Hospital, Harvard University, Belmont, MA) for donating the TH and DβH reporter constructs, and Dr. Erik Schweitzer (University of California, Los Angeles) for his kind donation of the inducible HD PC12 cell lines. This work was supported by NIH grants to J.-H.J.C. (R01 NS-38106) and K.E.V. (R01 GM-38931). J.-H.J.C. is also supported by The Coalition for the Cure (Huntington's Disease Society of America) and The Glendorn Foundation.",

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AU - Yohrling IV, George J.

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AU - DeJohn, Molly M.

AU - Miller, David W.

AU - Young, Anne B.

AU - Vrana, Kent E.

AU - Cha, Jang Ho J.

N1 - Funding Information: We would like to thank the Harvard Brain Tissue Resource Center for the human brain samples. They are supported in part by PHS grant MH/NS-31862. We would also like to thank Dr. Gillian Bates (King's College, London, UK) for generously supplying us with the R6/2 mice to perform these studies, Dr. Kwang-Soo Kim (McLean Hospital, Harvard University, Belmont, MA) for donating the TH and DβH reporter constructs, and Dr. Erik Schweitzer (University of California, Los Angeles) for his kind donation of the inducible HD PC12 cell lines. This work was supported by NIH grants to J.-H.J.C. (R01 NS-38106) and K.E.V. (R01 GM-38931). J.-H.J.C. is also supported by The Coalition for the Cure (Huntington's Disease Society of America) and The Glendorn Foundation.

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N2 - Huntington's disease (HD) is a progressive, autosomal dominant neurodegenerative disorder that is pathologically characterized by a striatal-specific degeneration. Aberrant dopamine neurotransmission has been proposed as a mechanism underlying the movement disorder of HD. We report that the enzymatic activity of tyrosine hydroxylase (TH), the rate-limiting enzyme for dopamine biosynthesis, is decreased in a transgenic mouse model of HD. In addition, mutant huntingtin was found to disrupt transcription of TH and dopamine β-hydroxylase (DβH) promoter reporter constructs. In situ hybridization revealed extensive loss of TH mRNA and decreased dopaminergic cell size in human HD substantia nigra. TH-immunoreactive protein was reduced in human grade 4 HD substantia nigra by 32% compared to age-matched controls. These findings implicate abnormalities in dopamine neurotransmission in HD and may provide new insights into targets for pharmacotherapy.

AB - Huntington's disease (HD) is a progressive, autosomal dominant neurodegenerative disorder that is pathologically characterized by a striatal-specific degeneration. Aberrant dopamine neurotransmission has been proposed as a mechanism underlying the movement disorder of HD. We report that the enzymatic activity of tyrosine hydroxylase (TH), the rate-limiting enzyme for dopamine biosynthesis, is decreased in a transgenic mouse model of HD. In addition, mutant huntingtin was found to disrupt transcription of TH and dopamine β-hydroxylase (DβH) promoter reporter constructs. In situ hybridization revealed extensive loss of TH mRNA and decreased dopaminergic cell size in human HD substantia nigra. TH-immunoreactive protein was reduced in human grade 4 HD substantia nigra by 32% compared to age-matched controls. These findings implicate abnormalities in dopamine neurotransmission in HD and may provide new insights into targets for pharmacotherapy.

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Analysis of cellular, transgenic and human models of Huntington's disease reveals tyrosine hydroxylase alterations and substantia nigra neuropathology

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