期刊
JOURNAL OF NEUROSCIENCE
卷 34, 期 2, 页码 418-433出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2712-13.2014
关键词
LRRK2; mechanisms; Parkinson's disease; single cell; synuclein
资金
- National Center for Research Resources Grant [RR18928]
- Hillblom Foundation
- Burroughs-Wellcome Medical Scientist Fund Career Award, NINDS [1K08NS062954-01A1]
- National Institute of Neurological Disorders and Stroke [P30NS069496]
- Intramural Research Program of the NIH, National Institute on Aging
- Koret/Taube Center
- Hellman Family Foundation
- [U24 NS078370]
- [3R01 NS039074]
- [2R01 NS04549]
- [2P01 AG0224074]
- [CIRM RB4-06079]
By combining experimental neuron models and mathematical tools, we developed a systems approach to deconvolve cellular mechanisms of neurodegeneration underlying the most common known cause of Parkinson's disease (PD), mutations in leucine-rich repeat kinase 2 (LRRK2). Neurons ectopically expressing mutant LRRK2 formed inclusion bodies (IBs), retracted neurites, accumulated synuclein, and died prematurely, recapitulating key features of PD. Degeneration was predicted from the levels of diffuse mutant LRRK2 that each neuron contained, but IB formation was neither necessary nor sufficient for death. Genetic or pharmacological blockade of its kinase activity destabilized LRRK2 and lowered its levels enough to account for the moderate reduction in LRRK2 toxicity that ensued. By contrast, targeting synuclein, including neurons made from PD patient-derived induced pluripotent cells, dramatically reduced LRRK2-dependent neurodegeneration and LRRK2 levels. These findings suggest that LRRK2 levels are more important than kinase activity per se in predicting toxicity and implicate synuclein as a major mediator of LRRK2-induced neurodegeneration.
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