2. Academic Validation
  3. Inhibition of p38α MAPK restores neuronal p38γ MAPK and ameliorates synaptic degeneration in a mouse model of DLB/PD

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

  • Sci Transl Med. 2023 May 10;15(695):eabq6089. doi: 10.1126/scitranslmed.abq6089.
Michiyo Iba 1,  Changyoun Kim 1,  Somin Kwon 1,  Marcell Szabo 1,  Liam Horan-Portelance 1,  Cody J Peer 2,  William D Figg 2,  Xylena Reed 3,  Jinhui Ding 4,  Seung-Jae Lee 5,  Robert A Rissman 6,  Mark R Cookson 3,  Cassia Overk 6,  Wolf Wrasidlo 6,  Eliezer Masliah 1 7
Affiliations

Affiliations

  • 1 Laboratory of Neurogenetics, Molecular Neuropathology Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
  • 2 Clinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 3 Laboratory of Neurogenetics, Cell Biology and Gene Expression Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
  • 4 Laboratory of Neurogenetics, Computational Biology Group, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
  • 5 Department of Biomedical Sciences, Neuroscience Research Institute, and Department of Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
  • 6 Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
  • 7 Division of Neuroscience, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
PMID: 37163617 DOI: 10.1126/scitranslmed.abq6089
Abstract

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.

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