Parkinson's Disease Modification Through Abl Kinase Inhibition: An Opportunity

Abstract

A BS TRACT: Parkinson's disease (PD) is the second most prevalent neurodegenerative disease of the central nervous system, with an estimated 5 000 000 cases worldwide. Historically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, PD pathology is now known to be widespread and to affect serotonin, cholinergic and norepinephrine neurons as well as nerve cells in the olfactory system, cerebral hemisphere, brain stem, spinal cord, and peripheral autonomic nervous system. PD pathology is characterized by the accumulation of misfolded α-synuclein, which is thought to play a critical role in the etiopathogenesis of the disease. Animal models of PD suggest that activation of the Abelson tyrosine kinase (c-Abl) plays an essential role in the initiation and progression of α-synuclein pathology and neurodegeneration. These studies demonstrate that internalization of misfolded α-synuclein activates c-Abl, which phosphorylates α-synuclein and promotes α-synuclein pathology within the affected neurons. Additionally, c-Abl inactivates parkin, disrupting mitochondrial quality control and biogenesis, promoting neurodegeneration. Post-mortem studies of PD patients demonstrate increased levels of tyrosine phosphorylated α-synuclein, consistent with the activation of c-Abl in human disease. Although the c-Abl inhibitor nilotinib failed to demonstrate clinical benefit in two double-blind trials, novel c-Abl inhibitors have been developed that accumulate in the brain and may inhibit c-Abl at saturating levels. These novel inhibitors have demonstrated benefits in animal models of PD and have now entered clinical development. Here, we review the role of c-Abl in the neurodegenerative disease process and consider the translational potential of c-Abl inhibitors from model studies to disease-modifying therapies for Parkinson's disease.

Nilotinib in Parkinson's disease: A systematic review and meta-analysis

“…Previous preclinical studies found that low doses of nilotinib had the ability to inhibit c-Abl, improve motor outcomes and CSF biomarker levels (Hebron et al, 2013a , b , 2014 ; Pagan et al, 2016 ). However, nilotinib does not appear these effects clinically because only a maximum of 10% of the concentration thought to be adequate to inhibit c-Abl was detected in the brain of PD patients (Pagan et al, 2019 ; Werner and Olanow, 2022 ). This may be interpreted by ATP-binding cassette (ABC) transporters which facilitate nilotinib removal from brain, therefore, nilotinib hardly achieves effective concentration to inhibit c-Abl.…”

“…Although dopamine replacement strategies, including levodopa, dopamine agonists and monoamine oxidase type B (MAO-B) inhibitors, are beneficial in the early stages of disease, they can't slow or stop disease progression (Balestrino and Schapira, 2020 ; Bloem et al, 2021 ). Moreover, long-term levodopa treatment relates to the development of motor complications such as fluctuations, dyskinesia and freezing, as well as other non-motor side-effects due to decreased tolerance (Balestrino and Schapira, 2020 ; Werner and Olanow, 2022 ). Slowing and stopping PD progression pathologically and reducing relevant clinical manifestations remain a major unmet need in the treatment of PD.…”

“…suggesting that c-Abl might be associated with PD progression and that its inhibitor nillotinib might have a potential benefit in treating PD. Subsequent studies found that nilotinib (1–10 mg/kg) could protect animal models of PD from neurodegeneration in the brain via inhibiting c-Abl, degrading α-synuclein and blocking inactivation of parkin (Hebron et al, 2013a , 2014 ; Karuppagounder et al, 2014 ; Lonskaya et al, 2014 ; Wu et al, 2021 ; Werner and Olanow, 2022 ). Researchers also found that nilotinib could improve motor behavior in PD models (Hebron et al, 2013a ).…”

Nonreceptor Tyrosine Kinase c-Abl-Mediated PHB2 Phosphorylation Aggravates Mitophagy Disorder in Parkinson’s Disease Model

“…In an MPTP-induced acute PD model, treatment of mice with STI 571 reduced the loss of dopaminergic neurons and ameliorated the locomotive defects by preventing p38 α phosphorylation [ 31 ]. A dual-blind clinical trial of the c-Abl inhibitor nilotinib failed to show its clinical efficacy in patients with PD [ 35 , 36 ], which is likely a result of incomplete inhibition of c-Abl activation [ 37 ]. The mounting evidence indicates that c-Abl has the potential to be a disease-modifying therapy for PD.…”

Molecular and Cellular Interactions in Pathogenesis of Sporadic Parkinson Disease

“…Compounds promising for the treatment of PD that increase the amount and/or activity of lysosomal glucocerebrosidase (GCase) have been synthesized, and include Ambroxol, Isofagomine, and NCGC607 [ 356 , 357 , 358 , 359 ]. Promising inhibitors of Abl Kinase (c-ABL) have also been synthesized, e.g., PD180970, Imatinib, and Nilotinib [ 360 , 361 , 362 , 363 ].…”