α-Synucleinopathy associated c-Abl activation causes p53-dependent autophagy impairment
Abstract Background Studies link c-Abl activation with the accumulation of pathogenic α-synuclein (αS) and neurodegeneration in Parkinson’s disease (PD). Currently, c-Abl, a tyrosine kinase activated by cellular stress, is thought to promote αS pathology by either directly phosphorylating αS or by c...
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| Format: | Article |
| Language: | English |
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BMC
2020-04-01
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| Series: | Molecular Neurodegeneration |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13024-020-00364-w |
| _version_ | 1818293733805785088 |
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| author | Md. Razaul Karim Elly E. Liao Jaekwang Kim Joyce Meints Hector Martell Martinez Olga Pletnikova Juan C. Troncoso Michael K. Lee |
| author_facet | Md. Razaul Karim Elly E. Liao Jaekwang Kim Joyce Meints Hector Martell Martinez Olga Pletnikova Juan C. Troncoso Michael K. Lee |
| author_sort | Md. Razaul Karim |
| collection | DOAJ |
| description | Abstract Background Studies link c-Abl activation with the accumulation of pathogenic α-synuclein (αS) and neurodegeneration in Parkinson’s disease (PD). Currently, c-Abl, a tyrosine kinase activated by cellular stress, is thought to promote αS pathology by either directly phosphorylating αS or by causing autophagy deficits. Methods αS overexpressing transgenic (Tg) mice were used in this study. A53T Tg mice that express high levels of human mutant A53TαS under the control of prion protein promoter. Two different approaches were used in this study. Natural aging and seeding model of synucleinopathy. In seeding model, intracortical/intrastriatal (IC/IS) stereotaxic injection of toxic lysates was done using tissue lysates from end-stage symptomatic mice. In this study, nilotinib and pifithrin-α was used as a c-Abl and p53 inhibitor, respectively. Both Tg and non-transgenic (nTg) mice from each group were subjected to nilotinib (10 mg/kg) or vehicle (DMSO) treatment. Frozen brain tissues from PD and control human cases were analyzed. In vitro cells study was implied for c-Abl/p53 genetic manipulation to uncover signal transduction. Results Herein, we show that the pathologic effects of c-Abl in PD also involve activation of p53, as c-Abl activation in a transgenic mouse model of α-synucleinopathy (TgA53T) and human PD cases are associated with the increased p53 activation. Significantly, active p53 in TgA53T neurons accumulates in the cytosol, which may lead to inhibition of autophagy. Thus, we hypothesized that c-Abl-dependent p53 activation contributes to autophagy impairment in α-synucleinopathy. In support of the hypothesis, we show that c-Abl activation is sufficient to inhibit autophagy in p53-dependent manner. Moreover, inhibition of either c-Abl, using nilotinib, or p53, using pifithrin-α, was sufficient to increase autophagic flux in neuronal cells by inducing phosphorylation of AMP-activated kinase (AMPK), ULK1 activation, and down-regulation of mTORC1 signaling. Finally, we show that pharmacological attenuation of c-Abl activity by nilotinib treatment in the TgA53T mouse model reduces activation of p53, stimulates autophagy, decreases accumulation αS pathology, and delays disease onset. Conclusion Collectively, our data show that c-Abl activation by α-synucleinopathy causes p53 dependent autophagy deficits and both c-Abl and p53 represent therapeutic target for PD. |
| first_indexed | 2024-12-13T03:20:33Z |
| format | Article |
| id | doaj.art-487df58d116947c79351cf1ed5aeac59 |
| institution | Directory Open Access Journal |
| issn | 1750-1326 |
| language | English |
| last_indexed | 2024-12-13T03:20:33Z |
| publishDate | 2020-04-01 |
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| series | Molecular Neurodegeneration |
| spelling | doaj.art-487df58d116947c79351cf1ed5aeac592022-12-22T00:01:22ZengBMCMolecular Neurodegeneration1750-13262020-04-0115111810.1186/s13024-020-00364-wα-Synucleinopathy associated c-Abl activation causes p53-dependent autophagy impairmentMd. Razaul Karim0Elly E. Liao1Jaekwang Kim2Joyce Meints3Hector Martell Martinez4Olga Pletnikova5Juan C. Troncoso6Michael K. Lee7Department of Neuroscience, University of MinnesotaDepartment of Neuroscience, University of MinnesotaDepartment of Neuroscience, University of MinnesotaDepartment of Neuroscience, University of MinnesotaDepartment of Neuroscience, University of MinnesotaDepartment of Pathology, Johns Hopkins University School of MedicineDepartment of Pathology, Johns Hopkins University School of MedicineDepartment of Neuroscience, University of MinnesotaAbstract Background Studies link c-Abl activation with the accumulation of pathogenic α-synuclein (αS) and neurodegeneration in Parkinson’s disease (PD). Currently, c-Abl, a tyrosine kinase activated by cellular stress, is thought to promote αS pathology by either directly phosphorylating αS or by causing autophagy deficits. Methods αS overexpressing transgenic (Tg) mice were used in this study. A53T Tg mice that express high levels of human mutant A53TαS under the control of prion protein promoter. Two different approaches were used in this study. Natural aging and seeding model of synucleinopathy. In seeding model, intracortical/intrastriatal (IC/IS) stereotaxic injection of toxic lysates was done using tissue lysates from end-stage symptomatic mice. In this study, nilotinib and pifithrin-α was used as a c-Abl and p53 inhibitor, respectively. Both Tg and non-transgenic (nTg) mice from each group were subjected to nilotinib (10 mg/kg) or vehicle (DMSO) treatment. Frozen brain tissues from PD and control human cases were analyzed. In vitro cells study was implied for c-Abl/p53 genetic manipulation to uncover signal transduction. Results Herein, we show that the pathologic effects of c-Abl in PD also involve activation of p53, as c-Abl activation in a transgenic mouse model of α-synucleinopathy (TgA53T) and human PD cases are associated with the increased p53 activation. Significantly, active p53 in TgA53T neurons accumulates in the cytosol, which may lead to inhibition of autophagy. Thus, we hypothesized that c-Abl-dependent p53 activation contributes to autophagy impairment in α-synucleinopathy. In support of the hypothesis, we show that c-Abl activation is sufficient to inhibit autophagy in p53-dependent manner. Moreover, inhibition of either c-Abl, using nilotinib, or p53, using pifithrin-α, was sufficient to increase autophagic flux in neuronal cells by inducing phosphorylation of AMP-activated kinase (AMPK), ULK1 activation, and down-regulation of mTORC1 signaling. Finally, we show that pharmacological attenuation of c-Abl activity by nilotinib treatment in the TgA53T mouse model reduces activation of p53, stimulates autophagy, decreases accumulation αS pathology, and delays disease onset. Conclusion Collectively, our data show that c-Abl activation by α-synucleinopathy causes p53 dependent autophagy deficits and both c-Abl and p53 represent therapeutic target for PD.http://link.springer.com/article/10.1186/s13024-020-00364-wNeurodegenerationParkinson’s disease (PD)α-SynucleinC-Ablp53Autophagy |
| spellingShingle | Md. Razaul Karim Elly E. Liao Jaekwang Kim Joyce Meints Hector Martell Martinez Olga Pletnikova Juan C. Troncoso Michael K. Lee α-Synucleinopathy associated c-Abl activation causes p53-dependent autophagy impairment Molecular Neurodegeneration Neurodegeneration Parkinson’s disease (PD) α-Synuclein C-Abl p53 Autophagy |
| title | α-Synucleinopathy associated c-Abl activation causes p53-dependent autophagy impairment |
| title_full | α-Synucleinopathy associated c-Abl activation causes p53-dependent autophagy impairment |
| title_fullStr | α-Synucleinopathy associated c-Abl activation causes p53-dependent autophagy impairment |
| title_full_unstemmed | α-Synucleinopathy associated c-Abl activation causes p53-dependent autophagy impairment |
| title_short | α-Synucleinopathy associated c-Abl activation causes p53-dependent autophagy impairment |
| title_sort | α synucleinopathy associated c abl activation causes p53 dependent autophagy impairment |
| topic | Neurodegeneration Parkinson’s disease (PD) α-Synuclein C-Abl p53 Autophagy |
| url | http://link.springer.com/article/10.1186/s13024-020-00364-w |
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