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PD-Like Pathogenesis in Caenorhabditis elegans Intestinally Infected with Nocardia farcinica and the Underlying Molecular Mechanisms

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Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the abnormal aggregation of α-synuclein (α-syn) and the loss of dopaminergic neurons. Although microbial infection has been implicated in the pathogenesis of PD, the associated virulence factors and the underlying molecular mechanisms require further elucidation. Here, we found that intestinal infection with Nocardia farcinica induced a series of PD-like symptoms in Caenorhabditis elegans, such as the accelerated degeneration of dopaminergic neurons, impaired locomotion capacity, and enhanced α-syn aggregation, through the disturbance of mitochondrial functions. To identify the potential virulence factors involved in these effects, we knocked out the nbtB/C and nbtS genes in N. farcinica, which are localized in the gene clusters responsible for nocobactin biosynthesis. The deletion of either gene partially rescued the degenerative effects of wild-type N. farcinica on dopaminergic neurons by attenuating mitochondrial dysfunction. LC–MS analysis further identified a decrease in the abundance of several siderophores in the two mutants, including nocobactin NA-a, nocobactin NA-b, and nocardimicin B. Collectively, our results demonstrated that intestinal N. farcinica infection in C. elegans facilitates PD-like pathogenesis and provides novel evidence for the involvement of pathogenic bacteria in neurodegenerative diseases via non-neuroinvasive mechanisms.

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No datasets were generated or analysed during the current study.

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Acknowledgements

The authors thank all the participants of the present study.

Funding

This work was supported by the National Natural Science Foundation Program of China (grant no. 32170184), the Department of Science and Technology of Yunnan Province (202403AC100007), and the Yunnan University Graduate Research Innovation Fund (KC-22221700).

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Author notes

  1. Wenwen Liu, Wenhui Zhou, and Peiji Zhao contribute equally to this paper.

Authors and Affiliations

  1. School of Medicine, Yunnan University, Kunming, 650091, China

    Wenwen Liu, Wenhui Zhou, Huan Gu, Yixin Li, Chidi Zhong, Hua Bai & Xiaowei Huang

  2. State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University, Kunming, 650091, China

    Peiji Zhao

  3. Neurosurgery of the Second Hospital Affiliated With Kunming Medical University, Kunming, 650101, China

    Tingting Wu & Ninghui Zhao

  4. College of Public Health, Kunming Medical University, Kunming, 650500, China

    Hua Bai

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  1. Wenwen Liu
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Contributions

All authors contributed to the study conception and design. Xiaowei Huang and Ninghui Zhao designed and supervised the entire process of the experiment and were the co-correspondent authors. Wenwen Liu, Wenhui Zhou and Peiji Zhao, co-first authors, carried out experiments with Tingting Wu, Huan Gu, and Yixin Li. Analysis of LC-MS data was conducted by Peiji Zhao. Statistical analysis was conducted by Chidi Zhong and Hua Bai. Wenwen Liu, Wenhui Zhou and Xiaowei Huang provided technical assistance reviewed and edited the manuscript. All authors reviewed the manuscript.

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Correspondence to Ninghui Zhao or Xiaowei Huang.

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Liu, W., Zhou, W., Zhao, P. et al. PD-Like Pathogenesis in Caenorhabditis elegans Intestinally Infected with Nocardia farcinica and the Underlying Molecular Mechanisms. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04076-w

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