Phosphorylation by the c-Abl protein tyrosine kinase inhibits Parkin’s ubiquitination and protective function

Neuroregeneration Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 09/2010; 107(38):16691-6. DOI: 10.1073/pnas.1006083107
Source: PubMed

ABSTRACT Mutations in PARK2/Parkin, which encodes a ubiquitin E3 ligase, cause autosomal recessive Parkinson disease (PD). Here we show that the nonreceptor tyrosine kinase c-Abl phosphorylates tyrosine 143 of parkin, inhibiting parkin's ubiquitin E3 ligase activity and protective function. c-Abl is activated by dopaminergic stress and by dopaminergic neurotoxins, 1-methyl-4-phenylpyridinium (MPP(+)) in vitro and in vivo by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), leading to parkin inactivation, accumulation of the parkin substrates aminoacyl-tRNA synthetase-interacting multifunctional protein type 2 (AIMP2) (p38/JTV-1) and fuse-binding protein 1 (FBP1), and cell death. STI-571, a c-Abl-family kinase inhibitor, prevents the phosphorylation of parkin, maintaining parkin in a catalytically active and protective state. STI-571's protective effects require parkin, as shRNA knockdown of parkin prevents STI-571 protection. Conditional knockout of c-Abl in the nervous system also prevents the phosphorylation of parkin, the accumulation of its substrates, and subsequent neurotoxicity in response to MPTP intoxication. In human postmortem PD brain, c-Abl is active, parkin is tyrosine-phosphorylated, and AIMP2 and FBP1 accumulate in the substantia nigra and striatum. Thus, tyrosine phosphorylation of parkin by c-Abl is a major posttranslational modification that inhibits parkin function, possibly contributing to pathogenesis of sporadic PD. Moreover, inhibition of c-Abl may be a neuroprotective approach in the treatment of PD.

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Available from: Bharathi Shrikanth Gadad, Aug 13, 2015
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    • "The pharmacological inhibition of c-Abl is also emerging as an attractive therapeutic strategy, as it was found to be neuroprotective in animal models of PD (Ko et al., 2010; Imam et al., 2011, 2013; Hebron et al., 2013a; Mahul-Mellier et al., 2014), by promoting aSyn degradation (Hebron et al., 2013a,b; Mahul- Mellier et al., 2014). Interestingly, c-Abl inhibition also targets hyperphosphorylated tau for degradation (Hebron et al., 2013a) and inhibits β-amyloid production in rat neuronal primary cultures and in guinea pig brains (Netzer et al., 2003). "
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    ABSTRACT: Protein misfolding and aggregation is a common hallmark in neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and fronto-temporal dementia (FTD). In these disorders, the misfolding and aggregation of specific proteins occurs alongside neuronal degeneration in somewhat specific brain areas, depending on the disorder and the stage of the disease. However, we still do not fully understand the mechanisms governing protein aggregation, and whether this constitutes a protective or detrimental process. In PD, alpha-synuclein (aSyn) forms protein aggregates, known as Lewy bodies, and is phosphorylated at serine 129. Other residues have also been shown to be phosphorylated, but the significance of phosphorylation in the biology and pathophysiology of the protein is still controversial. In AD and in FTD, hyperphosphorylation of tau protein causes its misfolding and aggregation. Again, our understanding of the precise consequences of tau phosphorylation in the biology and pathophysiology of the protein is still limited. Through the use of a variety of model organisms and technical approaches, we are now gaining stronger insight into the effects of phosphorylation in the behavior of these proteins. In this review, we cover recent findings in the field and discuss how targeting phosphorylation events might be used for therapeutic intervention in these devastating diseases of the nervous system.
    Frontiers in Molecular Neuroscience 05/2014; 7. DOI:10.3389/fnmol.2014.00042 · 4.08 Impact Factor
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    • "In this study, we provide a novel finding that in MPTP mice, striatal motor behaviors were normalized by systemic administration of nilotinib, a drug that is now clinically used to treat chronic myeloid leukemia (Weisberg et al., 2006; Blay and von Mehren, 2011). Together with the reported experimental findings that nilotinib (Hebron et al., 2013) and other c-Abl inhibitors (Ko et al., 2010; Imam et al., 2011, 2013) also play a protective role against the neurodegeneration of dopamine-producing cells in the substantia nigra of mice, our results suggest that nilotinib may serve as an alternative agent for attenuating motor symptoms and disease progression of PD. "
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    ABSTRACT: Abnormal motor behaviors in Parkinson's disease (PD) result from striatal dysfunction due to an imbalance between dopamine and glutamate transmissions that are integrated by dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32). c-Abelson tyrosine kinase (c-Abl) phosphorylates cyclin-dependent kinase 5 (Cdk5) at Tyr15 to increase the activity of Cdk5, which reduces the efficacy of dopaminergic signaling by phosphorylating DARPP-32 at Thr75 in the striatum. Here, we report that in the mouse striatum, a novel c-Abl inhibitor, nilotinib (AMN107), inhibits phosphorylation of both Cdk5 at Tyr15 and DARPP-32 at Thr75, which is negatively regulated by dopamine receptor activation through a D2 receptor-mediated mechanism. Like a D2-agonist, nilotinib synergizes with a D1-agonist for inducing striatal c-Fos expression. Moreover, systemic administration of nilotinib normalizes striatal motor behaviors in a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. These findings suggest that nilotinib could possibly serve as a new and alternative agent for treating PD motor symptoms.
    Frontiers in Cellular Neuroscience 02/2014; 8:50. DOI:10.3389/fncel.2014.00050 · 4.18 Impact Factor
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    • "Abl activation inhibits the E3 ubiquitin ligase activity of parkin, and Abl inhibition induces parkin protective function in Parkinson's disease (PD) models (Imam et al, 2011). Parkin is inactivated in the nigrostriatum of post‐mortem sporadic PD patients (Ko et al, 2010; Lonskaya et al, 2012a), and decreased parkin solubility is associated with defects in autophagic clearance of b‐ amyloid and p‐Tau in post‐mortem Alzheimer's disease (AD) brains (Lonskaya et al, 2012c). Parkin mediates autophagic degradation of defective mitochondria (mitophagy) (Geisler et al, 2010; Narendra et al, 2008; Park et al, 2009; Vives‐Bauza et al, 2010), and clears autophagic vacuoles (AVs) in AD and PD models (Khandelwal et al, 2011; Lonskaya et al, 2012a; Lonskaya et al, 2012c), while parkin deletion exacerbates amyloid pathology in AD models (Perucho et al, 2010; Rodriguez‐Navarro et al, 2008). "
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    ABSTRACT: Tyrosine kinase inhibitors (TKIs) are effective therapies for leukaemia. Alzheimer is a neurodegenerative disease characterized by accumulation of β-amyloid (plaques) and hyper-phosphorylated Tau (tangles). Here we show that AD animals have high levels of insoluble parkin and decreased parkin-Beclin-1 interaction, while peripheral administration of TKIs, including Nilotinib and Bosutinib, increases soluble parkin leading to amyloid clearance and cognitive improvement. Blocking Beclin-1 expression with shRNA or parkin deletion prevents tyrosine kinase (TK) inhibition-induced amyloid clearance, suggesting that functional parkin-Beclin-1 interaction mediates amyloid degradation. Isolation of autophagic vacuoles (AVs) in AD mouse brain shows accumulation of parkin and amyloid, consistent with previous results in AD brains, while Bosutinib and Nilotinib increase parkin-Beclin-1 interaction and result in protein deposition in the lysosome. These data suggest that decreased parkin solubility impedes parkin-Beclin-1 interaction and amyloid clearance. We identified two FDA-approved anti-cancer drugs as potential treatment for AD. Two FDA-approved tyrosine kinase inhibitor drugs, Bosutinib and Nilotinib, are shown to ameliorate Alzheimer's disease pathology in mouse models by increasing soluble parkin and leading to amyloid clearance and cognitive improvement.
    EMBO Molecular Medicine 08/2013; 5(8). DOI:10.1002/emmm.201302771 · 8.25 Impact Factor
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