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. 2017;7(4):589-601.
doi: 10.3233/JPD-171191.

c-Abl and Parkinson's Disease: Mechanisms and Therapeutic Potential

Saurav Brahmachari  1   2   3 , Senthilkumar S Karuppagounder  1   2   3 , Preston Ge  1   2   3 , Saebom Lee  1   2 , Valina L Dawson  1   2   4   5   3 , Ted M Dawson  1   2   5   6   3 , Han Seok Ko  1   5   7
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c-Abl and Parkinson's Disease: Mechanisms and Therapeutic Potential

Saurav Brahmachari et al. J Parkinsons Dis. 2017.

Abstract

Although the etiology of Parkinson's disease (PD) is poorly understood, oxidative stress has long been implicated in the pathogenesis of the disease. However, multifaceted and divergent signaling cascades downstream of oxidative stress have posed challenges for researchers to identify a central component of the oxidative stress-induced pathways causing neurodegeneration in PD. Since 2010, c-Abl-a non-receptor tyrosine kinase and an indicator of oxidative stress-has shown remarkable potential as a future promising drug target in PD therapeutics. Although, the constitutively active form of c-Abl, Bcr-Abl, has a long history in chronic myeloid leukemia and acute lymphocytic leukemia, the role of c-Abl in PD and relevant neurodegenerative diseases was completely unknown. Recently, others and we have identified and validated c-Abl as an important pathogenic mediator of the disease, where activated c-Abl emerges as a common link to various PD-related inducers of oxidative stress relevant to both sporadic and familial forms of PD and α-synucleinopathies. This review discusses the role of c-Abl in PD and the latest advancement on c-Abl as a drug target and as a prospective biomarker.

Keywords: Alpha-synuclein; Parkinson’s disease; biomarkers; c-Abl; c-Abl inhibitors; oxidative stress; parkin.

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Figures

Fig.1
Fig.1
c-Abl activation links diverse pathogenic pathways leading to neuronal death in response to oxidative stress in PD and related α-synucleinopathies. Mitochondrial dysfunction and resulting oxidative stress is the key feature in both sporadic PD and familial PD related α-synucleinopathies. c-Abl activation acts as a sensor of oxidative stress which in turn triggers multiple pathogenic signals primarily leading to inactivation of parkin, activation of p38α, NLRP3-inflammasome-mediated NF-κB activation in microglia, and α-synuclein phosphorylation at Y39. Parkin inactivation causes accumulation of pathogenic parkin substrates PARIS and AIMP2 and subsequently neuronal death. Activation of p38α and microglial activation of NF-κB merge on to cellular death. α-synuclein phosphorylation at Y39 is potentially linked to aggregation and neuronal toxicity.
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