(G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD

C. Y. Chen, Yi H. Weng, Kun Yi Chien, J. K. Lin, T. H. Yeh, Y. P. Cheng, C. S. Lu, H. L. Wang

Research output: Contribution to journalArticle

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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 Ser 257, and protein expression of active phospho-MKK4 Ser257 was upregulated in the SN of (G2019S) LRRK2 transgenic mice. Protein level of active phospho-JNK Thr183/Tyr185 and phospho-c-Jun Ser63, downstream targets of phospho-MKK4 Ser257, was increased in the SN of (G2019S) LRRK2 mice. Upregulated mRNA expression of pro-apoptotic Bim and FasL, target genes of phospho-c-Jun Ser63, 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.

Original languageEnglish
Pages (from-to)1623-1633
Number of pages11
JournalCell Death and Differentiation
Volume19
Issue number10
DOIs
Publication statusPublished - Oct 2012
Externally publishedYes

Fingerprint

MAP Kinase Kinase 2
MAP Kinase Signaling System
Dopaminergic Neurons
Leucine
Transgenic Mice
Parkinson Disease
Phosphotransferases
Mitogen-Activated Protein Kinase Kinases
jun Genes
MAP Kinase Kinase Kinases
Mutation
Caspase 9
Caspase 8
HEK293 Cells
Parkinsonian Disorders
Caspase 3
Signal Transduction
Proteins

Keywords

  • (G2019S) LRRK2
  • dopaminergic neurons
  • JNK
  • MKK4
  • Parkinson's disease

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

(G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD. / Chen, C. Y.; Weng, Yi H.; Chien, Kun Yi; Lin, J. K.; Yeh, T. H.; Cheng, Y. P.; Lu, C. S.; Wang, H. L.

In: Cell Death and Differentiation, Vol. 19, No. 10, 10.2012, p. 1623-1633.

Research output: Contribution to journalArticle

Chen, C. Y. ; Weng, Yi H. ; Chien, Kun Yi ; Lin, J. K. ; Yeh, T. H. ; Cheng, Y. P. ; Lu, C. S. ; Wang, H. L. / (G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD. In: Cell Death and Differentiation. 2012 ; Vol. 19, No. 10. pp. 1623-1633.
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AU - Weng, Yi H.

AU - Chien, Kun Yi

AU - Lin, J. K.

AU - Yeh, T. H.

AU - Cheng, Y. P.

AU - Lu, C. S.

AU - Wang, H. L.

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AB - (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 Ser 257, and protein expression of active phospho-MKK4 Ser257 was upregulated in the SN of (G2019S) LRRK2 transgenic mice. Protein level of active phospho-JNK Thr183/Tyr185 and phospho-c-Jun Ser63, downstream targets of phospho-MKK4 Ser257, was increased in the SN of (G2019S) LRRK2 mice. Upregulated mRNA expression of pro-apoptotic Bim and FasL, target genes of phospho-c-Jun Ser63, 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.

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