Apoptosis signal regulating kinase 1 deletion mitigates α-synuclein pre-formed fibril propagation in mice

Jie Zhang, Eun S. Park, Hye Jin Park, Run Yan, Magda Grudniewska, Xiaopei Zhang, Stephanie Oh, Xue Yang, Jean Baum, M. Maral Mouradian

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Abstract

α-Synuclein (α-Syn) is a key pathogenic protein in α-synucleinopathies including Parkinson disease and dementia with Lewy bodies. Accumulating evidence has shown that misfolded fibrillar α-Syn is transmitted from cell-to-cell, a phenomenon that correlates with clinical progression of the disease. We previously showed that deleting the MAP3 kinase apoptosis signal-regulating kinase 1 (ASK1), which is a central player linking oxidative stress with neuroinflammation, mitigates the phenotype of α-Syn transgenic mice. However, whether ASK1 impacts pathology and disease progression induced by recombinant α-Syn pre-formed fibrils (PFF) remains unknown. Here, we compared the neuropathological and behavioral phenotype of ASK1 knock-out mice with that of wild-type mice following intrastriatal injections of α-Syn PFF. At 6 months post-injections, ASK1 null mice exhibited reduced amount of phosphorylated α-Syn aggregates in the striatum and cortex, and less pronounced degeneration of the nigrostriatal pathway. Additionally, the neuroinflammatory reaction to α-Syn PFF injection and propagation seen in wild-type mice was attenuated in ASK1 knock-out animals. These neuropathological markers were associated with better behavioral performance. These data suggest that ASK1 plays an important role in pathological α-Syn fibril transmission and, consequently, may impact disease progression. These findings collectively support inhibiting ASK1 as a disease modifying therapeutic strategy for Parkinson disease and related α-synucleinopathies.

Original languageEnglish (US)
Pages (from-to)49-57
Number of pages9
JournalNeurobiology of Aging
Volume85
DOIs
Publication statusPublished - Jan 2020

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All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

Keywords

  • ASK1
  • Alpha-synuclein
  • Neuroinflammation
  • Parkinson disease
  • Pre-formed fibrils
  • Propagation

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