Parkinson's disease-implicated kinases in the brain; insights into disease pathogenesis

Abstract

Substantial evidence implicates abnormal protein kinase function in various aspects of Parkinson's disease (PD) etiology. Elevated phosphorylation of the PD-defining pathological protein, α-synuclein, correlates with its aggregation and toxic accumulation in neurons, whilst genetic missense mutations in the kinases PTEN-induced putative kinase 1 and leucine-rich repeat kinase 2, increase susceptibility to PD. Experimental evidence also links kinases of the phosphoinositide 3-kinase and mitogen-activated protein kinase signaling pathways, amongst others, to PD. Understanding how the levels or activities of these enzymes or their substrates change in brain tissue in relation to pathological states can provide insight into disease pathogenesis. Moreover, understanding when and where kinase dysfunction occurs is important as modulation of some of these signaling pathways can potentially lead to PD therapeutics. This review will summarize what is currently known in regard to the expression of these PD-implicated kinases in pathological human postmortem brain tissue.

Keywords: GAK; JNK; LRRK2; MAPK; PINK1; PLK; brain; kinase.

FIGURE 1

Kinases phosphorylating α-synuclein. The domain structure of α-synuclein showing phosphorylation at serine 129 by members of the polo-like kinase (PLK), casein kinase (CK), and G protein coupled receptor kinase (GRK) families. Pathogenic α-synuclein missense mutations are indicated with arrows.

FIGURE 2

Simplifed MAPK signaling. Receptor activation by growth factors or mitogens triggers a signal cascade in which mitogen activated protein kinase kinase kinases (MAPKKK) are activated and in turn activate mitogen activated kinase kinases (MAPKK) and then the mitogen activated protein kinases (MAPK), ERK, JNK, and P38. Evidence suggests that this pathway is upregulated in PD substantia nigra dopaminergic neurons, potentially contributing to cell death.

FIGURE 3

Simplified PI3K signaling. Receptor-ligand binding results in the activation of phosphoinositide 3-kinase (PI3K) that in turn mediates the conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 2,4,5-triphosphate (PIP3). PIP3 recruits protein kinase B (PKB) where it is activated by phosphorylation at Thr308 by phosphoinositide-dependent kinase 1 (PDK1) and Ser473 by mammalian target of rapamycin (mTOR) complex 2 (mTORC2). PKB then further phosphorylates downstream substrates to regulate cell survival and metabolic pathways. Evidence suggests reduced PKB but increased mTOR and GSK3β activity in PD, potentially contributing to protein accumulation and reduced cell survival.

FIGURE 4

Kinases implicated in Parkinson’s disease (PD). PD is characterized by the loss of pigmented dopaminergic neurons in the substantia nigra region of the midbrain. A number of biological processes have been implicated in this neuronal loss including mitochondrial dysfunction, oxidative stress, autophagy, and inflammation. In the substantia nigra, a number of kinases impacted by these processes combine to promote the accumulation of phosphorylated α -synuclein and induce conditions that reduce cell viability.