Kinases and kinase signaling pathways: Potential therapeutic targets in Parkinson's disease

Complex molecular mechanisms underlying the pathogenesis of Parkinson's disease (PD) are gradually being elucidated. Accumulating genetic evidence implicates dysfunction of kinase activities and phosphorylation pathways in the pathogenesis of PD. Causative and risk gene products associated with PD include protein kinases (such as PINK1, LRRK2 and GAK) and proteins related phosphorylation signaling pathways (such as SNCA, DJ-1). PINK1, LRRK2 and several PD gene products have been associated with mitogen-activated protein (MAP) and protein kinase B (AKT) kinase signaling pathways. C-Jun N-terminal kinase (JNK), extracellular signal-regulated kinases (ERK) and p38, signaling pathways downstream of MAP, are particularly important in PD. JNK and p38 play an integral role in neuronal death. Targeting JNK or p38 signaling may offer an effective therapy for PD. Inhibitors of the ERK signaling pathway, which plays an important role in the development of l-DOPA-induced dyskinesia (LID), have been shown to attenuate this condition in animal models. In this review, we summarize experimental evidence gathered over the last decade on the role of PINK1, LRRK2 and GAK and their related phosphorylation signaling pathways (JNK, ERK, p38 and PI3K/AKT) in PD. It is speculated that improvement or modulation of these signaling pathways will reveal potential therapeutic targets for attenuation of the cardinal symptoms and motor complications in patients with PD in the future.

► Accumulating genetic evidence implicates dysfunction of kinase activities and phosphorylation pathways in the pathogenesis of Parkinson's disease (PD).
► Causative and risk gene products protein kinases (PINK1, LRRK2 and GAK) and associated kinase signaling cascades (JNK/ERK/p38 and AKT pathways) associated with PD.
► JNK, ERK and p38, signaling pathways downstream of MAP, are particularly important in PD.
► JNK and p38 play an integral role in neuronal death, and targeting JNK or p38 signaling may offer an effective therapy for PD.
► Inhibitors of the ERK signaling pathway plays an important role in the development of LID in animal models.
► Studies on kinase signaling pathways not only improve our understanding of pathogenesis of PD, but also provide candidates for therapeutic intervention in PD patients.