Inhibition of mitogen-activated protein kinase and stimulation of Akt kinase signaling pathways: Two approaches with therapeutic potential in the treatment of neurodegenerative disease

Abstract

The neurodegenerative diseases of adulthood, including Alzheimer's disease (AD) and Parkinson's disease (PD), pose an enormous and growing public health burden. While effective symptomatic treatments exist for PD, and, to a lesser extent, for AD, there is no therapy for these disorders which will forestall their progression. With the rise of the concept of programmed cell death (PCD) came the realization that even in the absence of complete knowledge of proximate causes, neuroprotection may nevertheless be possible by targeting the pathways of PCD. One set of signaling pathways that have been implicated in cell death are the mitogen-activated protein kinase (MAPK) pathways. The possibility of blocking these pathways and thereby providing neuroprotection has recently been put to the test in a clinical trial of a mixed lineage kinase inhibitor in the treatment of PD. Unfortunately, this trial failed to demonstrate a protective effect. Based on considerations related to the implementation of the trial, it would be premature to conclude that inhibition of MAPK signaling is a failed strategy. In spite of these negative results, the MAPK and related kinase pathways retain their importance as potential targets in PD. In relation to pathogenesis, the discovery of mutations in the MLK-like kinase LRRK2 suggests a role for these kinases in regulating the viability of dopamine neurons. In relation to treatment, the survival signaling kinase Akt has been demonstrated in vivo to mediate striking neurotrophic and anti-apoptotic effects. Thus, it is likely that therapeutic targets related to these kinase signaling pathways will emerge.

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

“…The transcriptional activity of c-Jun is stimulated by JNK-mediated phosphorylation at Ser 63 , leading to increased expression of target genes that initiate the apoptotic cascade and caspase activation. 18,19 Western blot analysis using antiphospho-c-Jun Ser63 antibody demonstrated the expected upregulated expression of active phospho-c-Jun Ser63 in the SN of (G2019S) LRRK2 transgenic mice at 12 months of age (Figure 6a).…”

“…LRRK2 is believed to be a member of MLK subfamily of MAPKKKs. 18,19 MLKs are known to activate neuronal death signal pathway by phosphorylating downstream MKK4 at Ser 257 . Therefore, we hypothesized that (G2019S) LRRK2 displays an augmented kinase activity of phosphorylating MKK4 at Ser 257 .…”

“…[15][16][17] LRRK2 is believed to be a member of MLK subfamily of MAPKKKs, 6,7 and MLKs activate neuronal death signal pathway by phosphorylating downstream MKKs. 18,19 Previous in-vitro kinase assays reported that recombinant wild-type or (G2019S) LRRK2 phosphorylated MKK3, MKK4, MKK6, or MKK7 and that (G2019S) mutation augmented LRRK2-mediated phosphorylating of MKK6 or MKK7. 35,36 In the present study, our quantitative phosphoproteomic analysis identified MKK4 phosphorylated at Ser 257 residue as one of the upregulated phosphoproteins in the SN of (G2019S) LRRK2 mice, which are likely to be substrates of (G2019S) LRRK2-mediated phosphorylation in vivo (Chen et al, unpublished results).…”

“…Kinase domain of LRRK2 closely resembles that of mixed lineage kinases (MLKs), which are members of a large family of MAPKKKs and mediate cellular stress responses. 6,18,19 MLK family of MAPKKKs activates neuronal death signal pathway by phosphorylating and activating downstream MAPK kinases (MKKs), which subsequently induces the phosphorylation and activation of c-Jun N-terminal kinases (JNKs), essential mediators of neuronal death observed in various neurodegenerative diseases. 18,19 MKK4-JNK pathway has been shown to mediate the death of SNpc dopaminergic neurons caused by 6-hydroxydopamine injection and medial forebrain bundle axotomy, which are performed to prepare PD animal models.…”

“…6,18,19 MLK family of MAPKKKs activates neuronal death signal pathway by phosphorylating and activating downstream MAPK kinases (MKKs), which subsequently induces the phosphorylation and activation of c-Jun N-terminal kinases (JNKs), essential mediators of neuronal death observed in various neurodegenerative diseases. 18,19 MKK4-JNK pathway has been shown to mediate the death of SNpc dopaminergic neurons caused by 6-hydroxydopamine injection and medial forebrain bundle axotomy, which are performed to prepare PD animal models. 20,21 Thus, it is possible that (G2019S) LRRK2-induced aberrant activation of MKK4-JNK pathway causes degeneration of SNpc dopaminergic neurons.…”