We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
(G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD.
- Authors
Chen, C-Y; Weng, Y-H; Chien, K-Y; Lin, K-J; Yeh, T-H; Cheng, Y-P; Lu, C-S; Wang, H-L
- Abstract
(G2019S) mutation of leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause of both familial and sporadic Parkinson's disease (PD) cases. Twelve- to sixteen-month-old (G2019S) LRRK2 transgenic mice prepared by us displayed progressive degeneration of substantia nigra pars compacta (SNpc) dopaminergic neurons and parkinsonism phenotypes of motor dysfunction. LRRK2 is a member of mixed lineage kinase subfamily of mitogen-activated protein kinase kinase kinases (MAPKKKs). We hypothesized that (G2019S) mutation augmented LRRK2 kinase activity, leading to overphosphorylation of downstream MAPK kinase (MKK) and resulting in activation of neuronal death signal pathway. Consistent with our hypothesis, (G2019S) LRRK2 expressed in HEK 293 cells exhibited an augmented kinase activity of phosphorylating MAPK kinase 4 (MKK4) at Ser257, and protein expression of active phospho-MKK4Ser257 was upregulated in the SN of (G2019S) LRRK2 transgenic mice. Protein level of active phospho-JNKThr183/Tyr185 and phospho-c-JunSer63, downstream targets of phospho-MKK4Ser257, was increased in the SN of (G2019S) LRRK2 mice. Upregulated mRNA expression of pro-apoptotic Bim and FasL, target genes of phospho-c-JunSer63, and formation of active caspase-9, caspase-8 and caspase-3 were also observed in the SN of (G2019S) LRRK2 transgenic mice. Our results suggest that mutant (G2019S) LRRK2 activates MKK4-JNK-c-Jun pathway in the SN and causes the resulting degeneration of SNpc dopaminergic neurons in PD transgenic mice.
- Subjects
PARKINSON'S disease &; genetics; DOPAMINERGIC neurons; TRANSGENIC mice; PHENOTYPES; PHOSPHORYLATION
- Publication
Cell Death & Differentiation, 2012, Vol 19, Issue 10, p1623
- ISSN
1350-9047
- Publication type
Article
- DOI
10.1038/cdd.2012.42