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

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.

Cellular processes associated with LRRK2 function and dysfunction

“…LRRK2 was able to bind to and phosphorylate MAP2K, ‐3, ‐4, ‐6 and potentially ‐7 in vitro 70, 71. Furthermore, a G2019S ‐LRRK2 transgenic mouse model showed degeneration of dopaminergic neurons in the substantia nigra concomitant with hyperphosphorylation of MAP2K4 72. Activation of MAP2K3 and MAP2K6 is stimulated by stress, cytokines and growth factors, leading to the activation of the downstream effector p38.…”

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

“…Two transgenic mouse models overexpressing human G2019S LRRK2 exhibit modest age-dependent DA neuron loss associated with accumulation of autophagosomes and mitochondrial alterations [124,125], but other G2019S LRRK2 transgenic mouse models had diminished dopamine transmission and motor deficits without detectable neuron loss [53,54]. The only I2020T LRRK2 transgenic mouse model reported to date exhibits no obvious loss of DA neurons [126].…”

Studying neurodegenerative diseases in culture models

“…Indeed, consistent and permanent microglial activation and subsequent production of pro-inflammatory cytokines have been shown in primary microglial cells. [52][53][54][55][56][57][58] In particular, TLR4 may be crucial in activating microglial cells and may be involved in phagocytosis. 54 Another recently published study showed that oligomeric aSyn may interact and activate TLR2 in microglial cells.…”