2012年9月22日 電 /生物谷BIOON/ --近日,，一項最新研究揭示了退行性神經(jīng)系統(tǒng)疾病的患者為什么大腦細胞之間停止正常通信過程。
科學(xué)家們認為,，這一發(fā)現(xiàn)可以幫助大腦疾病如亨廷頓氏,、阿爾茨海默氏癥和帕金森氏病的治療。教授Tom Gillingwater領(lǐng)導(dǎo)的團隊分析了腦細胞之間信號連接是如何斷裂的,，并確定了控制該過程的6個重要蛋白質(zhì),。
在大腦細胞之間發(fā)送信號的連接點稱為突觸，因受傷或疾病可停止突觸的正常工作,，大腦的信號傳輸就會被中斷,，最終無法修復(fù)。
羅斯林研究所科學(xué)家在確定控制大腦之間信號傳輸?shù)?個重要蛋白質(zhì)后,，積極開發(fā)靶向這些蛋白質(zhì)的藥物,，希望找出能防止腦細胞之間通信故障的藥物。這項研究發(fā)表在PLoS Genetics雜志上,，由威康信托基金,、生物技術(shù)和生物科學(xué)研究理事會資助。（生物谷：Bioon.com）
doi:10.1371/journal.pgen.1002936
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Combining Comparative Proteomics and Molecular Genetics Uncovers Regulators of Synaptic and Axonal Stability and Degeneration In Vivo
Thomas M. Wishart, Timothy M. Rooney, Douglas J. Lamont, Ann K. Wright, A. Jennifer Morton, Mandy Jackson, Marc R. Freeman, Thomas H. Gillingwater*
Degeneration of synaptic and axonal compartments of neurons is an early event contributing to the pathogenesis of many neurodegenerative diseases, but the underlying molecular mechanisms remain unclear. Here, we demonstrate the effectiveness of a novel “top-down” approach for identifying proteins and functional pathways regulating neurodegeneration in distal compartments of neurons. A series of comparative quantitative proteomic screens on synapse-enriched fractions isolated from the mouse brain following injury identified dynamic perturbations occurring within the proteome during both initiation and onset phases of degeneration. In silico analyses highlighted significant clustering of proteins contributing to functional pathways regulating synaptic transmission and neurite development. Molecular markers of degeneration were conserved in injury and disease, with comparable responses observed in synapse-enriched fractions isolated from mouse models of Huntington's disease (HD) and spinocerebellar ataxia type 5. An initial screen targeting thirteen degeneration-associated proteins using mutant Drosophila lines revealed six potential regulators of synaptic and axonal degeneration in vivo. Mutations in CALB2, ROCK2, DNAJC5/CSP, and HIBCH partially delayed injury-induced neurodegeneration. Conversely, mutations in DNAJC6 and ALDHA1 led to spontaneous degeneration of distal axons and synapses. A more detailed genetic analysis of DNAJC5/CSP mutants confirmed that loss of DNAJC5/CSP was neuroprotective, robustly delaying degeneration in axonal and synaptic compartments. Our study has identified conserved molecular responses occurring within synapse-enriched fractions of the mouse brain during the early stages of neurodegeneration, focused on functional networks modulating synaptic transmission and incorporating molecular chaperones, cytoskeletal modifiers, and calcium-binding proteins. We propose that the proteins and functional pathways identified in the current study represent attractive targets for developing therapeutics aimed at modulating synaptic and axonal stability and neurodegeneration in vivo.
