Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of α-synuclein, and apoptotic cell death in aged mice

Tong Y.; Yamaguchi H.; Giaime E.Boyle S.Kopan R.Kelleher III R.J.Shen J.

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Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of α-synuclein, and apoptotic cell death in aged mice

机译：Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of α-synuclein, and apoptotic cell death in aged mice

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Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease. LRRK2 is a large protein containing a small GTPase domain and a kinase domain, but its physiological role is unknown. To identify the normal function of LRRK2 in vivo, we generated two independent lines of germ-line deletion mice. The dopaminergic system of LRRK2~(-/-) mice appears normal, and numbers of dopaminergic neurons and levels of striatal dopamine are unchanged. However, LRRK2~(-/-) kidneys, which suffer the greatest loss of LRRK compared with other organs, develop striking accumulation and aggregation of α-synuclein and ubiquitinated proteins at 20 months of age. The autophagy-lysosomal pathway is also impaired in the absence of LRRK2, as indicated by accumulation of lipofuscin granules aswell as altered levels of LC3-II and p62. Furthermore, loss of LRRK2 dramatically increases apoptotic cell death, inflammatory responses, and oxidative damage. Collectively, our findings show that LRRK2 plays an essential and unexpected role in the regulation of protein homeostasis during aging, and suggest that LRRK2 mutations may cause Parkinson's disease and cell death via impairment of protein degradation pathways, leading to α-synuclein accumulation and aggregation over time.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2010年第21期|9879-9884|共6页
作者
Tong Y.; Yamaguchi H.; Giaime E.Boyle S.Kopan R.Kelleher III R.J.Shen J.;
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作者单位

Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States;

Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States;

Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, United States;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
Aging; Autophagy; Knockout; Parkinson's disease; Ubiquitin-proteasome system;

Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of α-synuclein, and apoptotic cell death in aged mice

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