For many months, those who follow Parkinson’s disease clinical research have been anticipating the results of a small study of the cancer drug nilotinib. The study, now published in Journal of Parkinson’s Disease,¹ suggests that nilotinib and perhaps other

kinase inhibitors are worthy of more serious attention as treatments for Parkinson’s and related diseases. The “related diseases” part is important here because 5 of the 12 study participants were diagnosed with dementia with Lewy bodies.

But why study a cancer drug for Parkinson’s disease and Lewy body dementia? Is there a broader rationale for the use of kinase inhibitors in Parkinson’s disease? If double-blind, placebo-controlled studies of kinase inhibitors are successful—still a big question that may take years to answer—what can they tell us about disease pathology?

What Are Kinase Inhibitors?

As their name indicates, kinase inhibitors are designed to inhibit protein kinases. Kinases are enzymes that catalyze the addition of phosphate groups to other proteins. This phosphorylation activates or deactivates the target proteins, serving as an on or off signal for cellular functions such as molecular interactions, signal transduction, and localization within the cell.

Although kinases are essential to normal cellular function, problems can arise when they aren’t adequately regulated. One example is the blood cancer known as chronic myelogenous leukemia, which is usually caused by a genetic alteration in chromosomes 9 and 22. Parts of these chromosomes swap locations resulting in the so-called Philadelphia chromosome, a shortened chromosome 22 that contains the Abelson (ABL) gene from chromosome 9, which encodes a protein kinase. The translocated ABL gene is located near the Breakpoint Cluster Region (BCR) on the original chromosome 22 and the combination of these genes encodes a fusion protein that is a continuously activated ABL kinase.  The kinase is not deactivated by normal mechanisms, which in this case causes white blood cells to replicate out of control.  Nilotinib was developed to inhibit the BCR-ABL kinase and is used to treat chronic myelogenous leukemia.

Why Inhibit the BCR-ABL Kinase in Parkinson’s Disease?

People with Parkinson’s disease don’t have the Philadelphia chromosome or the BCR-ABL fusion protein, so why study nilotinib as a treatment? The answer goes back to one of the rare genetic causes of Parkinson’s disease—mutations in the parkin gene. Parkin is a ligase that ubiquitinates proteins, helping to regulate receptor trafficking and protein degradation though the ubiquitin pathway.^{2, 3}

In  2010, researchers at Johns Hopkins University reported that c-ABL phosphorylates parkin, which inhibits its ligase activity, leads to substrate accumulation, and interferes with its protection against MPP+ neurotoxicity.⁴ These results raised the possibility that c-ABL may be dysfunctional in Parkinson’s disease and suggested that its inhibition should be explored as a potential treatment. Subsequent studies further linked c-ABL to Parkinson’s and Alzheimer’s diseases.⁵

Other Kinases in Parkinson’s Disease

Several other kinases are even more notorious than c-ABL for their role in Parkinson’s disease. Selected mutations in leucine repeat rich kinase 2 (LRRK2) and PTEN-induced putative kinase (PINK1) cause Parkinson’s disease, with the former being much more common. Researchers are exploring LRRK2 inhibitors,⁶ but PINK1 mutations inactivate the enzyme,⁷ implying that medications targeting PINK1 would need to be kinase activators instead of inhibitors.

Given the success of kinase inhibitors in cancer, there is reason to hope that similar strategies could work in Parkinson’s disease. On the other hand, kinases do more than just one thing in the body, and inhibiting or activating them could have serious unintended consequences on other body systems. If nilotinib or other kinase based medications do prove to be useful in Parkinson’s disease, they may help researchers follow the trail of protein interactions that tie together key pathological components of Parkinson’s disease: genetic anomalies, alpha synuclein accumulation, and selective neuronal death.

References

1. Pagan F, Hebron M, Valadez EH, et al. Nilotinib Effects in Parkinson’s disease and Dementia with Lewy bodies. J Parkinsons Dis. Jul 11 2016.
2. Fallon L, Belanger CM, Corera AT, et al. A regulated interaction with the UIM protein Eps15 implicates parkin in EGF receptor trafficking and PI(3)K-Akt signalling. Nat Cell Biol. Aug 2006;8(8):834-842.
3. Ko HS, Kim SW, Sriram SR, Dawson VL, Dawson TM. Identification of far upstream element-binding protein-1 as an authentic Parkin substrate. J Biol Chem. Jun 16 2006;281(24):16193-16196.
4. Ko HS, Lee Y, Shin JH, et al. Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin’s ubiquitination and protective function. Proc Natl Acad Sci U S A. Sep 21 2010;107(38):16691-16696.
5. Schlatterer SD, Acker CM, Davies P. c-Abl in neurodegenerative disease. J Mol Neurosci. Nov 2011;45(3):445-452.
6. Taymans JM, Greggio E. LRRK2 Kinase Inhibition as a Therapeutic Strategy for Parkinson’s Disease, Where Do We Stand? Curr Neuropharmacol. 2016;14(3):214-225.
7. Cookson MR, Dauer W, Dawson T, Fon EA, Guo M, Shen J. The roles of kinases in familial Parkinson’s disease. J Neurosci. Oct 31 2007;27(44):11865-11868.