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

NEUROBIOLOGY OF AGING

卷:85

Article

Zhang, Jie^1,2  Park, Eun S.^1,2,4  Park, Hye-Jin^1,2,5  Yan, Run^1,2  Grudniewska, Magda^1,2  Zhang, Xiaopei^1,2  Oh, Stephanie^1,2  Yang, Xue³  Baum, Jean³  Mouradian, M. Maral^1,2 

[1] Robert Wood Johnson Med Sch, Inst Neurol Therapeut, Piscataway, NJ USA

[2] Rutgers Biomed & Hlth Sci, Dept Neurol, Piscataway, NJ USA

[3] Rutgers State Univ, Dept Chem & Chem Biol, Piscataway, NJ USA

[4] Univ Texas Hlth Sci Ctr Houston, Dept Neurosurg, Houston, TX 77030 USA

[5] CUNY, Adv Sci Res Ctr, New York, NY 10021 USA

关键词: ASK1;    Alpha-synuclein;    Pre-formed fibrils;    Propagation;    Parkinson disease;    Neuroinflammation;   

DOI  :  10.1016/j.neurobiolaging.2019.09.012

来源: Elsevier

【 摘 要 】

alpha-Synuclein (alpha-Syn) is a key pathogenic protein in alpha-synucleinopathies including Parkinson disease and dementia with Lewy bodies. Accumulating evidence has shown that misfolded fibrillar alpha-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 alpha-Syn transgenic mice. However, whether ASK1 impacts pathology and disease progression induced by recombinant alpha-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 alpha-Syn PFF. At 6 months post-injections, ASK1 null mice exhibited reduced amount of phosphorylated alpha-Syn aggregates in the striatum and cortex, and less pronounced degeneration of the nigrostriatal pathway. Additionally, the neuroinflammatory reaction to alpha-Syn PFF injection and propagation seen in wild-type mice was attenuated in ASK1 knockout animals. These neuropathological markers were associated with better behavioral performance. These data suggest that ASK1 plays an important role in pathological alpha-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 alpha-synucleinopathies. (C) 2019 Published by Elsevier Inc.

【 授权许可】

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