Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP

作者：Gomez Suaga Patricia; Luzon Toro Berta; Churamani Dev; Zhang Ling; Bloor Young Duncan; Patel Sandip; Woodman Philip G; Churchill Grant C; Hilfiker Sabine^*

来源：Human Molecular Genetics, 2012, 21(3): 511-525.

DOI：10.1093/hmg/ddr481

Mutations in the leucine-rich repeat kinase-2 (LRRK2) gene cause late-onset Parkinson's disease, but its physiological function has remained largely unknown. Here we report that LRRK2 activates a calcium-dependent protein kinase kinase-beta (CaMKK-beta)/ adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway which is followed by a persistent increase in autophagosome formation. Simultaneously, LRKR2 overexpression increases the levels of the autophagy receptor p62 in a protein synthesis-dependent manner, and decreases the number of acidic lysosomes. The LRRK2-mediated effects result in increased sensitivity of cells to stressors associated with abnormal protein degradation. These effects can be mimicked by the lysosomal Ca2+-mobilizing messenger nicotinic acid adenine dinucleotide phosphate (NAADP) and can be reverted by an NAADP receptor antagonist or expression of dominant-negative receptor constructs. Collectively, our data indicate a molecular mechanism for LRRK2 deregulation of autophagy and reveal previously unidentified therapeutic targets.

• 出版日期2012-2-1