Yu Wai Haung, Dorado Beatriz, Figueroa Helen Yvette, Wang Lili, Planel Emmanuel, Cookson Mark R, Clark Lorraine N, Duff Karen E
Dept of Pathology, Columbia University Medical Center, 630 W168th St Rm 12-461, New York NY 10032, USA.
Am J Pathol. 2009 Aug;175(2):736-47. doi: 10.2353/ajpath.2009.080928. Epub 2009 Jul 23.
Macroautophagy is an essential degradative pathway that can be induced to clear aggregated proteins, such as those found in Parkinson's disease and dementia with Lewy bodies, a form of Parkinsonism. This study found that both LC3-II and beclin were significantly increased in brains from humans with Dementia with Lewy bodies and transgenic mice overexpressing mutant alpha-synuclein, as compared with respective controls, suggesting that macroautophagy is induced to remove alpha-syn, particularly oligomeric or mutant forms. Aged mutant animals had higher autophagy biomarker levels relative to younger animals, suggesting that with aging, autophagy is less efficient and requires more stimulation to achieve the same outcome. Disruption of autophagy by RNA interference significantly increased alpha-syn oligomer accumulation in vitro, confirming the significance of autophagy in alpha-syn clearance. Finally, rotenone-induced alpha-syn aggregates were cleared following rapamycin stimulation of autophagy. Chronic rotenone exposure and commensurate reduction of metabolic activity limited the efficacy of rapamycin to promote autophagy, suggesting that cellular metabolism is critical for determining autophagic activity. Cumulatively, these findings support the concept that neuronal autophagy is essential for protein homeostasis and, in our system, reduction of autophagy increased the accumulation of potentially pathogenic alpha-synuclein oligomers. Aging and metabolic state were identified as important determinants of autophagic activity. This study provides therapeutic and pathological implications for both synucleinopathy and Parkinson's disease, identifying conditions in which autophagy may be insufficient to degrade alpha-syn aggregates.
巨自噬是一种重要的降解途径，可被诱导以清除聚集蛋白，如在帕金森病和路易体痴呆（一种帕金森综合征形式）中发现的那些蛋白。该研究发现，与各自的对照相比，路易体痴呆患者大脑以及过表达突变α-突触核蛋白的转基因小鼠大脑中，LC3-II和贝克林均显著增加，这表明巨自噬被诱导以清除α-突触核蛋白，特别是寡聚体或突变形式。与年轻动物相比，老年突变动物的自噬生物标志物水平更高，这表明随着年龄增长，自噬效率降低，需要更多刺激才能达到相同效果。通过RNA干扰破坏自噬在体外显著增加了α-突触核蛋白寡聚体的积累，证实了自噬在α-突触核蛋白清除中的重要性。最后，雷帕霉素刺激自噬后，鱼藤酮诱导的α-突触核蛋白聚集体被清除。长期鱼藤酮暴露和相应的代谢活性降低限制了雷帕霉素促进自噬的功效，表明细胞代谢对于确定自噬活性至关重要。总的来说，这些发现支持了神经元自噬对于蛋白质稳态至关重要的概念，并且在我们的系统中，自噬减少增加了潜在致病性α-突触核蛋白寡聚体的积累。衰老和代谢状态被确定为自噬活性的重要决定因素。这项研究为突触核蛋白病和帕金森病提供了治疗和病理方面的启示，确定了自噬可能不足以降解α-突触核蛋白聚集体的情况。
