Inhibition of p38α MAPK restores neuronal p38γ MAPK and ameliorates synaptic degeneration in a mouse model of DLB/PD

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 p38 alpha MAPK isoform and mis-localization of the p38 gamma MAPK isoform are associated with neuroinflammation and synaptic degeneration in DLB and PD. Therefore, we hypothesized that p38 alpha might be associated with neuronal p38 gamma distribution and syn-aptic 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 p38 alpha/beta, and then investi-gated the effects of this compound on p38 gamma and neurodegenerative pathology. We found that inhibition of p38 alpha reduced neuroinflammation and ameliorated synaptic, neurodegenerative, and motor behavioral deficits in transgenic mice overexpressing human alpha-synuclein. Moreover, treatment with SKF-86002 promoted the redis-tribution of p38 gamma to synapses and reduced the accumulation of alpha-synuclein in mice overexpressing human alpha-synuclein. Supporting the potential value of targeting p38 in DLB/PD, we found that SKF-86002 promoted the redistribution of p38 gamma in neurons differentiated from iPS cells derived from patients with familial PD (carrying the A53T alpha-synuclein mutation) and healthy controls. Treatment with SKF-86002 ameliorated alpha-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 alpha-synuclein-induced neurotoxicity, sug-gesting that SKF-86002 treatment inhibits alpha-synuclein-induced neurotoxicity mediated by microglia. These findings provide a mechanistic connection between p38 alpha and p38 gamma as well as a rationale for targeting this pathway in DLB/PD.

Automated summary

Alterations in p38 mitogen-activated protein kinases (MAPKs) are involved in the pathogenesis of dementia with Lewy bodies (DLB) and Parkinson's disease (PD). Inhibition of p38α reduces neuroinflammation and improves synaptic, neurodegenerative, and motor behavioral deficits. Treatment with SKF-86002 promotes the redistribution of p38γ to synapses and reduces accumulation of alpha-synuclein. These findings provide a mechanistic connection between p38α and p38γ and support targeting this pathway in DLB/PD.