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

Abstract

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.

Introduction

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by selective loss of dopaminergic neurons in the substantia nigra and formation of intracellular inclusions known as Lewy bodies in the remaining cells (Braak et al., 2004, Greenamyre and Hastings, 2004). Through identification of the genes involved in familial and sporadic PD during the past ten years, the pathogenesis of PD has been related to impairments of the ubiquitin–proteasome system (UPS) (Cook and Petrucelli, 2009, Matsuda and Tanaka, 2010), the autophagy-lysosome pathway (ALP) (Pan et al., 2008), mitochondrial metabolism disturbance (Cali et al., 2011, Ho et al., 2012) and alternated kinase activity (Cookson et al., 2007). Among these systems, the roles of kinases and kinase pathways have become an increasing focus of research and mutations in several genes encoding protein kinases and proteins involved in phosphorylation signaling pathways have been unequivocally linked to PD. Such protein kinases include PTEN-induced kinase 1 (PINK1) (Valente et al., 2001, Valente et al., 2004), leucine-rich repeat kinase 2 (LRRK2) (Funayama et al., 2002, Kumari and Tan, 2009) and Cyclin-G-associated kinase (GAK) (Dumitriu et al., 2011, Rhodes et al., 2011). These kinases, or their associated pathways, including mitogen-activated protein kinases (MAPK) such as extracellular signal-regulated protein kinases (ERK), c-Jun N-terminal kinases (JNK), p38 and protein kinase B/AKT are either risk factors associated pathological procedure or viable potential therapeutic targets (Cassarino et al., 2000, Harper and Wilkie, 2003, Silva et al., 2005, Borsello and Forloni, 2007, Karunakaran et al., 2008, Dagda et al., 2009). Other PD-associated PARK genes, such as SNCA (PARK1/4), Parkin (PARK2), DJ-1 (PARK7), GIGYF2 (PARK11) and HTRA2 (PARK13) have been shown to function in kinase signaling related pathways (Alnemri, 2007, Schapira, 2009, Carballo-Carbajal et al., 2010, Higashi et al., 2010, Akundi et al., 2012). These further emphasize the importance of reviewing kinase encoded PARK genes (LRRK2, PINK1 and GAK) and their linked kinase pathways such as JNK, ERK, p38 and protein kinase B/AKT signaling pathways, which could serve as potential targets for therapeutic intervention in PD.