Bodner Ruth A, Outeiro Tiago Fleming, Altmann Stephen, Maxwell Michele M, Cho Stephanie H, Hyman Bradley T, McLean Pamela J, Young Anne B, Housman David E, Kazantsev Aleksey G
Center for Cancer Research, Massachusetts Institute of Technology, Room E18-505, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Proc Natl Acad Sci U S A. 2006 Mar 14;103(11):4246-51. doi: 10.1073/pnas.0511256103. Epub 2006 Mar 6.
Misfolded proteins accumulate in many neurodegenerative diseases, including huntingtin in Huntington's disease and alpha-synuclein in Parkinson's disease. The disease-causing proteins can take various conformations and are prone to aggregate and form larger cytoplasmic or nuclear inclusions. One approach to the development of therapeutic intervention for these diseases has been to identify chemical compounds that reduce the size or number of inclusions. We have, however, identified a compound that promotes inclusion formation in cellular models of both Huntington's disease and Parkinson's disease. Of particular interest, this compound prevents huntingtin-mediated proteasome dysfunction and reduces alpha-synuclein-mediated toxicity. These results demonstrate that compounds that increase inclusion formation may actually lessen cellular pathology in both Huntington's and Parkinson's diseases, suggesting a therapeutic approach for neurodegenerative diseases caused by protein misfolding.
错误折叠的蛋白质在许多神经退行性疾病中积累，包括亨廷顿舞蹈病中的亨廷顿蛋白和帕金森病中的α-突触核蛋白。致病蛋白可呈现多种构象，易于聚集并形成更大的细胞质或核内包涵体。针对这些疾病开发治疗干预措施的一种方法是鉴定能够减小包涵体大小或数量的化合物。然而，我们已经鉴定出一种在亨廷顿舞蹈病和帕金森病的细胞模型中促进包涵体形成的化合物。特别有趣的是，这种化合物可防止亨廷顿蛋白介导的蛋白酶体功能障碍，并降低α-突触核蛋白介导的毒性。这些结果表明，增加包涵体形成的化合物实际上可能减轻亨廷顿舞蹈病和帕金森病中的细胞病理学变化，这为蛋白质错误折叠引起的神经退行性疾病提出了一种治疗方法。
