c-Abl Inhibitors Enable Insights into the Pathophysiology and Neuroprotection in Parkinson's Disease

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder causing movement disabilities and several non-motor symptoms in afflicted patients. Recent studies in animal models of PD and analyses of brain specimen from PD patients revealed an increase in the level and activity of the non-receptor tyrosine kinase Abelson (c-Abl) in dopaminergic neurons with phosphorylation of protein substrates, such as α-synuclein and the E3 ubiquitin ligase, Parkin. Most significantly inhibition of c-Abl kinase activity by small molecular compounds used in the clinic to treat human leukemia have shown promising neuroprotective effects in cell and animal models of PD. This has raised hope that similar beneficial outcome may also be observed in the treatment of PD patients by using c-Abl inhibitors. Here we highlight the background for the current optimism, reviewing c-Abl and its relationship to pathophysiological pathways prevailing in PD, as well as discussing issues related to the pharmacology and safety of current c-Abl inhibitors. Clearly more rigorously controlled and well-designed trials are needed before the c-Abl inhibitors can be used in the neuroclinic to possibly benefit an increasing number of PD patients.

Keywords: Parkinson’s disease; c-Abl; leukemia; nilotinib; parkin; α-synuclein.

Figure 1

The role of c-Abl in pathophysiological events in Parkinson’s disease (PD). Schematic view of the structure and action of c-Abl in neurons. c-Abl contains the protein kinase region and the SH2 and SH3 domains. The activity of the protein is tightly regulated in cells by intramolecular and other interactions and by the Src family kinases Lyn and Fyn. In addition, increased oxidative stress involving mitochondria can activate c-Abl leading to subsequent phosphorylation of downstream targets. In the neurons α-synuclein form intracellular aggregates called Lewy bodies and this process is aggravated after phosphorylation by c-Abl. Parkin is an ubiquitin ligase that regulates the mitochondrial biogenesis via the PARkin Interacting Substrate (Paris) and the transcriptional coactivator Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) Parkin also controls mitochondrial dynamics and mitophagy. Phosphorylation by c-Abl inactivates Parkin leading to mitochondrial alterations and an increased oxidative stress. This may cause further activation of c-Abl producing a vicious cycle in the neuron with an enhanced cell degeneration to follow. c-Abl inhibitors may potentially hinder this cascade by reducing the amount of α-synuclein aggregates and by restoring the functions of Parkin and of other substrates. Some of the c-Abl inhibitors are known to block also the Src family kinases and may thus theoretically be more neuroprotective. A challenge for the c-Abl inhibitors is that these drugs may not effectively pass the blood-brain barrier (BBB) possibly limiting their use in PD and other brain disorders.