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 language | English |
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Pages (from-to) | 49-57 |
Number of pages | 9 |
Journal | Neurobiology of Aging |
Volume | 85 |
DOIs | |
Publication status | Published - 1 Jan 2020 |
Externally published | Yes |
Funding
The authors would like to thank Hidenori Ichijo (University of Tokyo) for providing ASK1 knock-out mice, and acknowledge the technical assistance from Gina M. Moriarty in Jean Baum’s laboratory (Rutgers University) with purifying recombinant mouse α-synuclein from plasmid pT7-7 originally obtained from Peter Lansbury. Mouradian is the William Dow Lovett Professor of Neurology and is supported by the Michael J. Fox Foundation for Parkinson's Research, the American Parkinson Disease Association, the New Jersey Health Foundation/Nicholson Foundation , and by grants from the US National Institutes of Health (NIH) ( AT006868 , NS073994 , NS096032 , and NS101134 ). Baum is supported by National Institutes of Health grant GM110577 . The remaining authors have no actual or potential conflicts of interest. Author contributions: Zhang contributed to experimental design, carried out experiments, analyzed and interpreted data, and drafted the manuscript; E.S. Park contributed to experimental design, carried out experiments, and analyzed and interpreted data; H.J. Park carried out experiments, and analyzed and interpreted data; Yan, Zhang, and Yang carried out experiments and analyzed data; Grudniewska, Oh, and Baum analyzed and interpreted data; and Mouradian contributed to experimental design, analyzed and interpreted data, and wrote the manuscript. Appendix A
Keywords
- Alpha-synuclein
- ASK1
- Neuroinflammation
- Parkinson disease
- Pre-formed fibrils
- Propagation