Dopaminergic neuron loss and up-regulation of chaperone protein mRNA induced by targeted over-expression of alpha-synuclein in mouse substantia nigra.

Dopaminergic neuron loss and up-regulation of chaperone protein mRNA induced by targeted over-expression of alpha-synuclein in mouse substantia nigra. Research Abstract Details 

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Dopaminergic neuron loss and up-regulation of chaperone protein mRNA induced by targeted over-expression of alpha-synuclein in mouse substantia nigra. Abstract Text:

Jessie L St Martin,Jochen Klucken,Tiago F Outeiro,Paul Nguyen,Christine Keller-McGandy,Ippolita Cantuti-Castelvetri,Tom N Grammatopoulos,David G Standaert,Bradley T Hyman,Pamela J McLean,

Several transgenic mouse lines with altered alpha-synuclein expression have been developed that show a variety of Parkinson's disease-like symptoms without specific loss of dopaminergic neurons. Targeted over-expression of human alpha-synuclein using viral-vector mediated gene delivery into the substantia nigra of rats and non-human primates leads to dopaminergic cell loss and the formation of alpha-synuclein aggregates reminiscent of Lewy bodies. In the context of these recent findings, we used adeno-associated virus (AAV) to over-express wild type human alpha-synuclein in the substantia nigra of mice. We hypothesized that this over-expression would recapitulate pathological hallmarks of Parkinson's disease, creating a mouse model to further characterize the disease pathogenesis. Recombinant AAV expressing alpha-synuclein was stereotaxically injected into the substantia nigra of mice, leading to a 25% reduction of dopaminergic neurons after 24 weeks of transduction. Furthermore, examination of mRNA levels of stress-related proteins using laser capture microdissection and quantitative PCR revealed a positive correlation of Hsp27 expression with the extent of viral transduction at 4 weeks and a positive correlation of Hsp40, Hsp70 and caspase 9 with the extent of viral transduction at 24 weeks. Taken together, our findings suggest that targeted over-expression of alpha-synuclein can induce pathology at the gross anatomical and molecular level in the substantia nigra, providing a mouse model in which upstream changes in Parkinson's disease pathogenesis can be further elucidated.

Dopaminergic neuron loss and up-regulation of chaperone protein mRNA induced by targeted over-expression of alpha-synuclein in mouse substantia nigra. Publishing Authors By Initials

JL St Martin,J Klucken,TF Outeiro,P Nguyen,C Keller-McGandy,I Cantuti-Castelvetri,TN Grammatopoulos,DG Standaert,BT Hyman,PJ McLean,

For similar proteins: nerve tissue proteins: synucleins: alpha-synuclein research abstracts see: proteins: nerve tissue proteins: synucleins: alpha-synuclein research

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Dopaminergic neuron loss and up-regulation of chaperone protein mRNA induced by targeted over-expression of alpha-synuclein in mouse substantia nigra. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Journal of neurochemistry

VOLUME: 100

Page Numbers: 1449-57

Journal Abbreviation: J. Neurochem.

ISSN: 0022-3042

DAY: 4

MONTH: 01

YEAR: 2007

Dopaminergic neuron loss and up-regulation of chaperone protein mRNA induced by targeted over-expression of alpha-synuclein in mouse substantia nigra. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 2985190

Dopaminergic neuron loss and up-regulation of chaperone protein mRNA induced by targeted over-expression of alpha-synuclein in mouse substantia nigra. Keywords Mesh Terms:

KEYWORDS: alpha-Synuclein

MESH TERMS: metabolism

Chemical & Substance for Abstract: Dopaminergic neuron loss and up-regulation of chaperone protein mRNA induced by targeted over-expression of alpha-synuclein in mouse substantia nigra. Information

Substance Name: Tyrosine 3-Monooxygenase

Registry Number: EC 1.14.16.2

Grant and Affiliation Information for Dopaminergic neuron loss and up-regulation of chaperone protein mRNA induced by targeted over-expression of alpha-synuclein in mouse substantia nigra.

AFFILIATION: Alzheimer's Disease Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.

Country: England

AGENCY: United States NINDS

GRANT: P50 NS38372

ACRONYM: NS

MEDLINETA: J Neurochem

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