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Effects of Lanthionine Ketimine-5-Ethyl Ester on the α-Synucleinopathy Mouse Model

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Abstract

Potentially druggable mechanisms underlying synaptic deficits seen in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are under intense interrogations. In addition to defective synaptic vesicle trafficking, cytoskeletal disruption, autophagic perturbation, and neuroinflammation, hyperphosphorylation of microtubule-associated protein collapsin response mediator protein 2 (CRMP2, also known as DPYSL2) is newly determined to correlate with synaptic deficits in human DLB. The small molecule experimental therapeutic, lanthionine ketimine-5-ethyl ester (LKE), appears to interact with CRMP2 in a host of neurodegenerative mouse models, normalizing its phosphorylation level while promoting healthful autophagy in cell culture models and suppressing the proinflammatory phenotype of activated microglia. Accordingly, this study examined the effect of LKE on α-synuclein A53T transgenic (Tg) mice which were employed as a DLB model. We found that chronic administration of LKE to A53T mice suppressed (1) the accumulation of LBs, (2) neuroinflammatory activation of microglia, (3) impairment of contextual fear memory, and (4) CRMP2 phosphorylation at Thr509 in A53T Tg mice. These results suggest that CRMP2 phosphorylation by GSK3β in the hippocampus is related to pathology and memory impairment in DLB, and LKE may have clinical implications in the treatment of α-synucleinopathy.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon request.

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Funding

This work was supported by Grants-in-Aid for Scientific Research on Priority Areas from The Ministry of Education, Culture, Sports, Science and Technology (no. 26430043 to T.O).

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Authors and Affiliations

  1. Department of Life Science and Medical Bioscience, Waseda University, Shinjuku-ku, Tokyo, 162-8480, Japan

    Arina Yazawa & Toshio Ohshima

  2. Department of Biochemistry, Molecular and Cell Science, Arkansas College of Osteopathic Medicine (ARCOM), Fort Smith, AR, 72916, USA

    Kenneth Hensley

  3. Laboratory for Molecular Brain Science, Department of Life Science and Medical Bioscience, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo, 162-8480, Japan

    Toshio Ohshima

Authors
  1. Arina Yazawa
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  2. Kenneth Hensley
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Contributions

Conceptualization: TO; Formal analysis and investigation: AY; Writing—original draft preparation: AY; Writing—review and editing: KH, TO; Funding acquisition: TO; Resources: KH; Supervision: TO. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Toshio Ohshima.

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Conflict of interest

KH is the inventor of patented LK derivatives used in this study, and own equity in a company involved with commercial development of the compounds for neurodegenerative disease.

Ethical Approval

All animal experiments were conducted in accordance with the technical protocols for animal experiments approved by the Institutional Animal Care and Use Committee at Waseda University.

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Yazawa, A., Hensley, K. & Ohshima, T. Effects of Lanthionine Ketimine-5-Ethyl Ester on the α-Synucleinopathy Mouse Model. Neurochem Res 47, 2373–2382 (2022). https://doi.org/10.1007/s11064-022-03626-9

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  • DOI: https://doi.org/10.1007/s11064-022-03626-9

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