The p75 neurotrophin receptor as a novel intermediate in L-dopa-induced dyskinesia in experimental Parkinson's disease.

Zhihua Liu, Aijuan Yan, Jiahao Zhao, Shuyuan Yang, Lu Song, Zhenguo Liu

Experimental neurology 2021 Aug

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In Parkinson's disease (PD), long-term administration of L-dopa often leads to L-dopa-induced dyskinesia (LID), a debilitating motor complication. The p75 neurotrophin receptor (p75NTR) is likely to play a critical role in the regulation of dendritic spine density and morphology and appears to be associated with neuroinflammation, which previously has been identified as a crucial mechanism in LID. While aberrant modifications of p75NTR in neurological diseases have been extensively documented, only a few studies report p75NTR dysfunction in PD, and no data are available in LID. Here, we explored the functional role of p75NTR in LID. In LID rats, we identified that p75NTR was significantly increased in the lesioned striatum. In 6-hydroxydopamine (6-OHDA)-hemilesioned rats, specific knockdown of striatal p75NTR levels achieved by viral vector injection into the striatum prevented the development of LID and increased striatal structural plasticity. By contrast, we found that in 6-OHDA-hemilesioned rats, striatal p75NTR overexpression exacerbated LID and facilitated striatal dendritic spine losses. Moreover, we observed that the immunomodulatory drug fingolimod attenuated LID without lessening the therapeutic efficacy of L-dopa and normalized p75NTR levels. Together, these data demonstrate for the first time that p75NTR plays a pivotal role in the development of LID and that p75NTR may act as a potential novel target for the management of LID. Copyright © 2021 Elsevier Inc. All rights reserved.

Citation

Zhihua Liu, Aijuan Yan, Jiahao Zhao, Shuyuan Yang, Lu Song, Zhenguo Liu. The p75 neurotrophin receptor as a novel intermediate in L-dopa-induced dyskinesia in experimental Parkinson's disease. Experimental neurology. 2021 Aug;342:113740