Gene expression changes presage neurodegeneration in a Drosophila model of Parkinson's disease

被引:86
作者
Scherzer, CR
Jensen, RV
Gullans, SR
Feany, MB
机构
[1] Harvard Univ, Sch Med, Dept Pathol, Brigham & Womens Hosp, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Ctr Neurol Dis, Brigham & Womens Hosp, Cambridge, MA 02319 USA
[3] Wesleyan Univ, Dept Phys, Middletown, CT 06457 USA
关键词
D O I
10.1093/hmg/ddg265
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Transgenic Drosophila expressing human alpha-synuclein faithfully replicate essential features of human Parkinson's disease, including age-dependent loss of dopaminergic neurons, Lewy-body-like inclusions and locomotor impairment. To define the transcriptional program encoding molecular machinery involved in alpha-synuclein pathology, we characterized expression of the entire Drosophila genome at pre-symptomatic, early and advanced disease stages. Fifty-one signature transcripts, including lipid, energy and membrane transport mRNAs, were tightly associated with alpha-synuclein expression. Most importantly, at the pre-symptomatic stage, when the potential for neuroprotection is greatest, expression changes revealed specific pathology. In age-matched tau transgenic Drosophila, the transcription of alpha-synuclein associated genes was normal, suggesting highly distinct pathways of neurodegeneration. Temporal profiling of progressive gene expression changes in neurodegenerative disease models provides unbiased starting points for defining disease mechanisms and for identifying potential targets for neuroprotective drugs at pre-clinical stages.
引用
收藏
页码:2457 / 2466
页数:10
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