2. Academic Validation
  3. Inhibiting TRPV4 improves α-synuclein degradation through autophagy-lysosomal pathway in the MPP+-induced cell model of parkinson's disease

Inhibiting TRPV4 improves α-synuclein degradation through autophagy-lysosomal pathway in the MPP+-induced cell model of parkinson's disease

  • Sci Rep. 2025 Nov 27;15(1):42443. doi: 10.1038/s41598-025-26513-z.
Yuncheng Bai # 1 2,  Hui Zang # 3,  Zhengbin Chen 4,  Renwan Yin 2,  Wenjing Yang 2,  Jia Luo 2,  Qingjie Ma 5,  Na Liu 6
Affiliations

Affiliations

  • 1 Department of Orthopedic Surgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China.
  • 2 Faculty of Medical Science, Kunming University of Science and Technology, Kunming, China.
  • 3 Department of Anesthesiology, Kunming City Women and Children Hospital, Kunming, China.
  • 4 Department of Critical Care Medicine, The Second People's Hospital of Baoshan city, Yunnan Province, China.
  • 5 Department of Anesthesiology and Surgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, No. 157 Jinbi Road, Kunming, China. [email protected].
  • 6 Department of Anesthesiology and Surgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, No. 157 Jinbi Road, Kunming, China. [email protected].
  • # Contributed equally.
PMID: 41309756 DOI: 10.1038/s41598-025-26513-z
Abstract

Parkinson's disease (PD) is a prevalent neurodegenerative disorder often accompanied by dementia in its advanced stages. The pathogenesis of PD dementia involves abnormal Autophagy and the accumulation of phosphorylated at serine 129 α-synuclein (pS129 α-syn). Proper functioning of the autophagy-lysosomal pathway (ALP) is essential for the effective degradation of pS129 α-syn. Our previous studies implicated the Calcium Channel transient receptor potential vanilloid 4 (TRPV4) in dopaminergic neuron degeneration by demonstrating that its overexpression induces endoplasmic reticulum stress and inflammation, driving neuronal loss-a hallmark of PD. This study aimed to investigate the role of TRPV4 in ALP-mediated pS129 α-syn clearance in the 1-methyl-4-phenylpyridinium ion (MPP+)-induced PC12 cells. We observed that MPP+ upregulated TRPV4 expression, reduced cell viability, and increased pS129 α-syn levels. Critically, all these effects were reversed by TRPV4 siRNA. Furthermore, TRPV4 siRNA restored cellular autophagic flux, which was impaired by MPP+. Treatment with either TRPV4 siRNA or TRPV4 special inhibitor HC067047 attenuated the MPP+-induced elevation of microtubule associated protein 1 light chain 3B (LC3B) and p62, while restoring the expression of lysosome-associated membrane protein 1 (LAMP1) and mature Cathepsin D - key indicators of ALP functionality. These results suggest that TRPV4 silencing enhances α-syn degradation via the ALP, highlighting its potential as a therapeutic target for PD.

Keywords

Autophagy-lysosomal pathway; Parkinson’s disease; TRPV4; Α-synuclein.

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