Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Mol Neurodegener. 2009 Jul 23;4:32. doi: 10.1186/1750-1326-4-32.
Lewy bodies and Lewy neurites constitute the cardinal neuropathological features of both Parkinson's disease (PD) and Lewy body dementia (LBD). Whereas alpha-synuclein has been found to be the major component of the Lewy body, the mechanisms by which neurons degenerate, as well as basic mechanisms involved in the formation of alpha-synuclein-related inclusions, remain obscure. We have suggested previously that potential mechanisms are likely to leave a "molecular signature" or protein adduct within the Lewy body, and have found examples of such signatures in previous studies. In this study, we demonstrate increased FOXO3 in association with Lewy bodies and Lewy neurites in LBD and PD brain tissue. Since FOXO proteins are involved in several pathways responsible for the regulation of cell death, cell proliferation, and cell metabolism, the ectopic localization of FOXO3 to Lewy bodies provides evidence that aberrations in basic cellular biochemistry may contribute to inclusion formation, which is likely more complex than a simple "gain of function" toxicity as is commonly opined. In light of the known interaction of FOXO3 and 14-3-3, basic protein-protein interaction between these proteins and alpha-synuclein may be key.
路易体和路易神经纤维构成了帕金森病 (PD) 和路易体痴呆 (LBD) 的主要神经病理学特征。虽然已经发现α-突触核蛋白是路易体的主要成分，但神经元退化的机制以及与α-突触核蛋白相关包涵体形成的基本机制仍不清楚。我们之前曾提出，潜在的机制可能会在路易体中留下“分子特征”或蛋白质加合物，并在之前的研究中找到了这种特征的例子。在这项研究中，我们发现在 LBD 和 PD 脑组织中，与路易体和路易神经纤维相关的 FOXO3 增加。由于 FOXO 蛋白参与了几个负责细胞死亡、细胞增殖和细胞代谢调节的途径，FOXO3 异位定位于路易体提供了证据，表明基本细胞生物化学的异常可能导致包涵体的形成，这可能比通常认为的简单“获得功能”毒性更为复杂。鉴于已知的 FOXO3 和 14-3-3 的相互作用，这些蛋白质与α-突触核蛋白之间的基本蛋白质-蛋白质相互作用可能是关键。
