Protein Kinases and Parkinson's Disease

Abstract

Currently, the lack of new drug candidates for the treatment of major neurological disorders such as Parkinson's disease has intensified the search for drugs that can be repurposed or repositioned for such treatment. Typically, the search focuses on drugs that have been approved and are used clinically for other indications. Kinase inhibitors represent a family of popular molecules for the treatment and prevention of various cancers, and have emerged as strong candidates for such repurposing because numerous serine/threonine and tyrosine kinases have been implicated in the pathobiology of Parkinson's disease. This review focuses on various kinase-dependent pathways associated with the expression of Parkinson's disease pathology, and evaluates how inhibitors of these pathways might play a major role as effective therapeutic molecules.

Keywords: Parkinson’s disease; dopamine; kinase inhibitors; serine/threonine kinase; tyrosine kinase.

Figure 1

In response to various stressors, c-Jun N-terminal kinase (JNK) is activated and phosphorylates c-Jun, which increases the activity of activating protein-1 (AP-1). AP-1 modulates the transcription genes such as Fas ligand (FasL) to induce apoptosis via an extrinsic pathway. JNK also appears to activate non-nuclear substrates (such as Bcl-2 family members) to promote cell death via an intrinsic pathway. 6-OHDA: 6-hydroxydopamine.

Figure 2

Phosphorylated c-Abl tyrosine phosphorylates parkin at Y143, which leads to the loss of ubiquitin-ligase activity, the accumulation of toxic parkin substrates, and neuronal death. AIMP2: aminoacyl tRNA synthetase complex-interacting multifunctional protein 2; FBP: far up stream element binding protein.