期刊
CELL
卷 157, 期 2, 页码 472-485出版社
CELL PRESS
DOI: 10.1016/j.cell.2014.01.064
关键词
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资金
- Merck KGAA
- National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) [P50NS038377]
- JPB Foundation
- MDSCRF [2007-MSCRFI-0420-00, 2009-MSCRFII-0125-00, 2013-MSCRFII-0105-00]
- NIH/NINDS [P50 NS072187]
- New York Stem Cell Foundation-Druckenmiller Fellowship
Mutations in leucine-rich repeat kinase 2 (LRRK2) are a common cause of familial and sporadic Parkinson's disease (PD). Elevated LRRK2 kinase activity and neurodegeneration are linked, but the phosphosubstrate that connects LRRK2 kinase activity to neurodegeneration is not known. Here, we show that ribosomal protein s15 is a key pathogenic LRRK2 substrate in Drosophila and human neuron PD models. Phosphodeficient s15 carrying a threonine 136 to alanine substitution rescues dopamine neuron degeneration and age-related locomotor deficits in G2019S LRRK2 transgenic Drosophila and substantially reduces G2019S LRRK2-mediated neurite loss and cell death in human dopamine and cortical neurons. Remarkably, pathogenic LRRK2 stimulates both cap-dependent and cap-independent mRNA translation and induces a bulk increase in protein synthesis in Drosophila, which can be prevented by phosphodeficient T136A s15. These results reveal a novel mechanism of PD pathogenesis linked to elevated LRRK2 kinase activity and aberrant protein synthesis in vivo.
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