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Activation of tyrosine kinase c-Abl contributes to ?-synuclein-induced neurodegeneration.

ABSTRACT: Aggregation of ?-synuclein contributes to the formation of Lewy bodies and neurites, the pathologic hallmarks of Parkinson disease (PD) and ?-synucleinopathies. Although a number of human mutations have been identified in familial PD, the mechanisms that promote ?-synuclein accumulation and toxicity are poorly understood. Here, we report that hyperactivity of the nonreceptor tyrosine kinase c-Abl critically regulates ?-synuclein-induced neuropathology. In mice expressing a human ?-synucleinopathy-associated mutation (hA53T?-syn mice), deletion of the gene encoding c-Abl reduced ?-synuclein aggregation, neuropathology, and neurobehavioral deficits. Conversely, overexpression of constitutively active c-Abl in hA53T?-syn mice accelerated ?-synuclein aggregation, neuropathology, and neurobehavioral deficits. Moreover, c-Abl activation led to an age-dependent increase in phosphotyrosine 39 ?-synuclein. In human postmortem samples, there was an accumulation of phosphotyrosine 39 ?-synuclein in brain tissues and Lewy bodies of PD patients compared with age-matched controls. Furthermore, in vitro studies show that c-Abl phosphorylation of ?-synuclein at tyrosine 39 enhances ?-synuclein aggregation. Taken together, this work establishes a critical role for c-Abl in ?-synuclein-induced neurodegeneration and demonstrates that selective inhibition of c-Abl may be neuroprotective. This study further indicates that phosphotyrosine 39 ?-synuclein is a potential disease indicator for PD and related ?-synucleinopathies.

SUBMITTER: Brahmachari S

PROVIDER: S-EPMC4966315 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Activation of tyrosine kinase c-Abl contributes to α-synuclein-induced neurodegeneration.

Brahmachari Saurav S Ge Preston P Lee Su Hyun SH Kim Donghoon D Karuppagounder Senthilkumar S SS Kumar Manoj M Mao Xiaobo X Shin Joo Ho JH Lee Yunjong Y Pletnikova Olga O Troncoso Juan C JC Dawson Valina L VL Dawson Ted M TM Ko Han Seok HS

The Journal of clinical investigation 20160627 8

Aggregation of α-synuclein contributes to the formation of Lewy bodies and neurites, the pathologic hallmarks of Parkinson disease (PD) and α-synucleinopathies. Although a number of human mutations have been identified in familial PD, the mechanisms that promote α-synuclein accumulation and toxicity are poorly understood. Here, we report that hyperactivity of the nonreceptor tyrosine kinase c-Abl critically regulates α-synuclein-induced neuropathology. In mice expressing a human α-synucleinopath ...[more]

PMID: 27348587

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Project description:Background In the ongoing battle against BCR-ABL+ leukemia, despite significant advances with tyrosine kinase inhibitors (TKIs), the persistent challenges of drug resistance and the enduring presence of leukemic stem cells (LSCs) remain formidable barriers to achieving a cure. Methods In this study, we demonstrated that Disulfiram (DSF) induces ferroptosis to synergize with TKIs in inhibiting BCR-ABL+ cells, particularly targeting resistant cells and LSCs, using cell models, mouse models, and primary cells from patients. We elucidated the mechanism by which DSF promotes GPX4 degradation to induce ferroptosis through immunofluorescence, co-immunoprecipitation (CO-IP), RNA sequencing, lipid peroxidation assays, and rescue experiments. Results Here, we present compelling evidence elucidating the sensitivity of DSF, an FDA-approved drug for alcohol dependence, towards BCR-ABL+ cells. Our findings underscore DSF's ability to selectively induce a potent cytotoxic effect on BCR-ABL+ cell lines and effectively inhibit primary BCR-ABL+ leukemia cells. Crucially, the combined treatment of DSF with TKIs selectively eradicates TKI-insensitive stem cells and resistant cells. Of particular note is DSF's capacity to disrupt GPX4 stability, elevate the labile iron pool, and intensify lipid peroxidation, ultimately leading to ferroptotic cell death. Our investigation shows that BCR-ABL expression induces alterations in cellular iron metabolism and increases GPX4 expression. Additionally, we demonstrate the indispensability of GPX4 for LSC development and the initiation/maintenance of BCR-ABL+ leukemia. Mechanical analysis further elucidates DSF's ability to circumvent resistance by reducing GPX4 levels through the disruption of its binding with HSPA8, thereby promoting GPX4 ubiquitination and subsequent degradation. Furthermore, the combined treatment of DSF with TKIs effectively targets both BCR-ABL+ blast cells and drug-insensitive LSCs, conferring a significant survival advantage in mouse models. Conclusion In summary, the dual inhibition of GPX4 and BCR-ABL presents a promising therapeutic strategy to synergistically target blast cells and drug-insensitive LSCs in patients, offering potential avenues for advancing leukemia treatment.

Dataset Information

Activation of tyrosine kinase c-Abl contributes to ?-synuclein-induced neurodegeneration.

Publications

Activation of tyrosine kinase c-Abl contributes to α-synuclein-induced neurodegeneration.

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