| Autor: |
Iba, Michiyo, Kim, Changyoun, Kwon, Somin, Szabo, Marcell, Horan-Portelance, Liam, Peer, Cody J., Figg, William D., Reed, Xylena, Ding, Jinhui, Lee, Seung-Jae, Rissman, Robert A., Cookson, Mark R., Overk, Cassia, Wrasidlo, Wolf, Masliah, Eliezer |
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| Zdroj: |
Science Translational Medicine; 5/10/2023, Vol. 15 Issue 695, p1-15, 15p |
| Abstrakt: |
Alterations in the p38 mitogen-activated protein kinases (MAPKs) play an important role in the pathogenesis of dementia with Lewy bodies (DLB) and Parkinson's disease (PD). Activation of the p38α MAPK isoform and mislocalization of the p38γ MAPK isoform are associated with neuroinflammation and synaptic degeneration in DLB and PD. Therefore, we hypothesized that p38α might be associated with neuronal p38γ distribution and synaptic dysfunction in these diseases. To test this hypothesis, we treated in vitro cellular and in vivo mouse models of DLB/PD with SKF-86002, a compound that attenuates inflammation by inhibiting p38α/β, and then investigated the effects of this compound on p38γ and neurodegenerative pathology. We found that inhibition of p38α reduced neuroinflammation and ameliorated synaptic, neurodegenerative, and motor behavioral deficits in transgenic mice overexpressing human α-synuclein. Moreover, treatment with SKF-86002 promoted the redistribution of p38γ to synapses and reduced the accumulation of α-synuclein in mice overexpressing human α-synuclein. Supporting the potential value of targeting p38 in DLB/PD, we found that SKF-86002 promoted the redistribution of p38γ in neurons differentiated from iPS cells derived from patients with familial PD (carrying the A53T α-synuclein mutation) and healthy controls. Treatment with SKF-86002 ameliorated α-synuclein–induced neurodegeneration in these neurons only when microglia were pretreated with this compound. However, direct treatment of neurons with SKF-86002 did not affect α-synuclein–induced neurotoxicity, suggesting that SKF-86002 treatment inhibits α-synuclein–induced neurotoxicity mediated by microglia. These findings provide a mechanistic connection between p38α and p38γ as well as a rationale for targeting this pathway in DLB/PD. p38α MAPK inhibition to ameliorate Lewy body diseases: p38 mitogen-activated protein kinases are associated with neuroinflammation and neurodegeneration. Inhibitors of p38α MAPK are currently in clinical trials for Alzheimer's disease (AD). Iba and colleagues tested whether the p38α inhibitor SKF-86002 could ameliorate Lewy body diseases (LBDs), a group of diseases that includes dementia with Lewy bodies (DLB) and idiopathic Parkinson's disease (PD). Treatment with SKF-86002 inhibited α-synuclein accumulation, restored synaptic p38γ MAPK, and corrected behavioral deficits in a mouse model of DLB/PD. SKF-86002 also reduced pathology in neurons derived from patients with PD. These results indicate that p38α inhibitors could be a potential therapeutic strategy for LBDs. —DN [ABSTRACT FROM AUTHOR] |
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Complementary Index |
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