期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 109, 期 40, 页码 16119-16124出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1206286109
关键词
aging; neurodegeneration; proteinopathy
资金
- National Institutes of Neurological Disorders and Stroke [NS057656]
- Parkinson's Disease Resource of Northwest Louisiana
Parkinson disease (PD) results from the slow, progressive loss of dopaminergic neurons in the substantia nigra. Alterations in alpha-synuclein (aSyn), such as mutations or multiplications of the gene, are thought to trigger this degeneration. Here, we show that aSyn disrupts mitogen-activated protein kinase (MAPK)controlled stress signaling in yeast and human cells, which results in inefficient cell protective responses and cell death. aSyn is a substrate of the yeast (and human) polo-like kinase Cdc5 (Plk2), and elevated levels of aSyn prevent Cdc5 from maintaining a normal level of GTP-bound Rho1, which is an essential GTPase that regulates stress signaling. The nine N-terminal amino acids of aSyn are essential for the interaction with polo-like kinases. The results support a unique mechanism of PD pathology.
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