2013
DOI: 10.1093/hmg/ddt192
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Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of  -synuclein in Parkinson's disease models

Abstract: Parkinson's disease is a movement disorder characterized by death of dopaminergic substantia nigra (SN) neurons and brain accumulation of α-synuclein. The tyrosine kinase Abl is activated in neurodegeneration. Here, we show that lentiviral expression of α-synuclein in the mouse SN leads to Abl activation (phosphorylation) and lentiviral Abl expression increases α-synuclein levels, in agreement with Abl activation in PD brains. Administration of the tyrosine kinase inhibitor nilotinib decreases Abl activity and… Show more

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Cited by 290 publications
(359 citation statements)
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“…[9][10][11] The c-Abl inhibitor Nilotinib and INNO-406 have been reported prevents the loss of dopamine neurons and improves motor behavior in a murine PD model. [12][13][14] In this study, we demonstrated that c-Abl is activated in oxidative stress-induced PD. Both the conditional knockout (KO) of c-Abl and treatment with the c-Abl inhibitor STI571 protect against MPTP-induced PD.…”
supporting
confidence: 52%
See 1 more Smart Citation
“…[9][10][11] The c-Abl inhibitor Nilotinib and INNO-406 have been reported prevents the loss of dopamine neurons and improves motor behavior in a murine PD model. [12][13][14] In this study, we demonstrated that c-Abl is activated in oxidative stress-induced PD. Both the conditional knockout (KO) of c-Abl and treatment with the c-Abl inhibitor STI571 protect against MPTP-induced PD.…”
supporting
confidence: 52%
“…25 Recently, extensive studies have been performed on c-Abl in the nervous system to investigate its role in neurodegenerative disease. [9][10][11][12][13][14]26 For example, c-Abl kinase has been reported to regulate the accumulation of AIMP2 (aminoacyl tRNA synthetase complex-interacting multifunctional protein 2), FBP1 (far upstream elementbinding protein 1), and α-synuclein in PD models. 9,10,11 Here, by using the SILAC analysis, we identified p38α as a major Figure 6 The p38α inhibitor SB203580 protects against MPTP-induced dopaminergic neuronal death and motor deficits.…”
Section: Discussionmentioning
confidence: 99%
“…Overactivation of c-Abl is emerging as a consistent feature of sporadic PD (23,25,(46)(47)(48). c-Abl levels as well as markers of c-Abl activity are increased in sporadic PD (23,25,(46)(47)(48).…”
Section: Discussionmentioning
confidence: 99%
“…c-Abl is activated in human postmortem PD brain in the striatum and substantia nigra (23,24). Recently, there have been a few reports indicating that c-Abl inhibition might be beneficial in PD and α-synucleinopathies (23,25,26). However, the lack of selectivity of the c-Abl inhibitors used in these studies has made it difficult to conclude whether c-Abl inhibition could be an effective neuroprotective strategy.…”
Section: Introductionmentioning
confidence: 99%
“…One example of an AMPK activator with therapeutic potential in neurodegenerative disease is metformin (commonly used in type 2 diabetes) (112). Nilotinib, which has been shown to be protective in multiple mouse models of neurodegeneration through different mechanisms (113,114), can also induce autophagy via AMPK activation (115). Dual class I PI3K/mTORC1 inhibitors such as PI103 are potent mTOR-dependent autophagy inducers, which address the negative feedback between mTORC1 and the class I PI3K/AKT pathway (116).…”
Section: Autophagy Upregulation As Therapy For Neurodegenerative Diseasementioning
confidence: 99%