PMID- 35093118 OWN - NLM STAT- MEDLINE DCOM- 20220407 LR - 20220531 IS - 1742-2094 (Electronic) IS - 1742-2094 (Linking) VI - 19 IP - 1 DP - 2022 Jan 29 TI - TRPV4 contributes to ER stress and inflammation: implications for Parkinson's disease. PG - 26 LID - 10.1186/s12974-022-02382-5 [doi] LID - 26 AB - BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder. Its molecular mechanism is still unclear, and pharmacological treatments are unsatisfactory. Transient receptor potential vanilloid 4 (TRPV4) is a nonselective Ca(2+) channel. It has recently emerged as a critical risk factor in the pathophysiology of neuronal injuries and cerebral diseases. Our previous study reported that TRPV4 contributed to endoplasmic reticulum (ER) stress in the MPP(+)-induced cell model of PD. In the present study, we detected the role and the mechanism of TRPV4 in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice. METHODS: Intracerebral injection of an adeno-associated virus (AAV) into the substantia nigra (SN) of mice was used to knockdown or upregulate the expression of TRPV4 and intraperitoneal injection of MPTP. Rotarod and pole tests were used to evaluate the locomotor ability of mice. We used immunohistochemistry, Nissl staining and Western blot to detect the alterations in the number of tyrosine hydroxylase (TH)-positive neurons, Nissl-positive neurons, the levels of ER stress-associated molecules and proinflammatory cytokines in the SN. RESULTS: The SN was transfected with AAV for 3 weeks and expressed the target protein with green fluorescence. Knockdown of TRPV4 via injection of a constructed AAV-TRPV4 shRNAi into the SN alleviated the movement deficits of PD mice. Upregulation of TRPV4 via injection of a constructed AAV-TRPV4 aggravated the above movement disorders. The expression of TRPV4 was upregulated in the SN of MPTP-treated mice. Injection of AAV-TRPV4 shRNAi into the SN rescued the number of TH-positive and Nissl-positive neurons in the SN decreased by MPTP, while injection of AAV-TRPV4 induced the opposite effect. Moreover, MPTP-decreased Sarco/endoplasmic reticulum Ca(2+)-ATPase 2 (SERCA2) and pro-cysteinyl aspartate specific proteinase-12 (procaspase-12), MPTP-increased Glucose-regulated protein 78 (GRP78), Glucose-regulated protein 94 (GRP94) and C/EBP homologous protein (CHOP) were inhibited by AAV-TRPV4 shRNAi infection, and enhanced by AAV-TRPV4. In the same way, MPTP-decreased procaspase-1, MPTP-increased Interleukin-18 (IL-18), Cyclooxgenase-2 (COX-2) and 5-Lipoxygenase (5-LOX) were inhibited by AAV-TRPV4 shRNAi, or further exacerbated by AAV-TRPV4. CONCLUSIONS: These results suggest that TRPV4 mediates ER stress and inflammation pathways, contributing to the loss of dopamine (DA) neurons in the SN and movement deficits in PD mice. Moreover, this study provides a new perspective on molecular targets and gene therapies for the treatment of PD in the future. CI - (c) 2022. The Author(s). FAU - Liu, Na AU - Liu N AD - Medical School, Kunming University of Science and Technology, No.727 Jingming South Road, Kunming, 650500, China. AD - Department of Anesthesiology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, China. FAU - Bai, Liping AU - Bai L AD - Medical School, Kunming University of Science and Technology, No.727 Jingming South Road, Kunming, 650500, China. FAU - Lu, Zhipeng AU - Lu Z AD - Medical School, Kunming University of Science and Technology, No.727 Jingming South Road, Kunming, 650500, China. FAU - Gu, Rou AU - Gu R AD - Medical School, Kunming University of Science and Technology, No.727 Jingming South Road, Kunming, 650500, China. FAU - Zhao, Dongdong AU - Zhao D AD - Medical School, Kunming University of Science and Technology, No.727 Jingming South Road, Kunming, 650500, China. FAU - Yan, Fang AU - Yan F AD - Medical School, Kunming University of Science and Technology, No.727 Jingming South Road, Kunming, 650500, China. FAU - Bai, Jie AU - Bai J AUID- ORCID: 0000-0003-1281-3159 AD - Medical School, Kunming University of Science and Technology, No.727 Jingming South Road, Kunming, 650500, China. jiebai662001@126.com. LA - eng GR - 1097821401/The Yunling Scholar/ GR - U2002220/National Natural Science Foundation of China/ PT - Journal Article DEP - 20220129 PL - England TA - J Neuroinflammation JT - Journal of neuroinflammation JID - 101222974 RN - 0 (TRPV Cation Channels) RN - 0 (Trpv4 protein, mouse) RN - 9P21XSP91P (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine) SB - IM MH - 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/pharmacology MH - Animals MH - Disease Models, Animal MH - Dopaminergic Neurons MH - Inflammation/chemically induced/metabolism MH - *MPTP Poisoning/metabolism MH - Mice MH - Mice, Inbred C57BL MH - *Parkinson Disease/metabolism MH - Substantia Nigra/metabolism MH - TRPV Cation Channels/genetics/metabolism PMC - PMC8800324 OTO - NOTNLM OT - ER stress OT - Inflammation OT - MPTP OT - Parkinson's disease OT - SN OT - TRPV4 COIS- All the authors declared no competing financial interests. EDAT- 2022/01/31 06:00 MHDA- 2022/04/08 06:00 PMCR- 2022/01/29 CRDT- 2022/01/30 20:27 PHST- 2021/04/22 00:00 [received] PHST- 2022/01/10 00:00 [accepted] PHST- 2022/01/30 20:27 [entrez] PHST- 2022/01/31 06:00 [pubmed] PHST- 2022/04/08 06:00 [medline] PHST- 2022/01/29 00:00 [pmc-release] AID - 10.1186/s12974-022-02382-5 [pii] AID - 2382 [pii] AID - 10.1186/s12974-022-02382-5 [doi] PST - epublish SO - J Neuroinflammation. 2022 Jan 29;19(1):26. doi: 10.1186/s12974-022-02382-5.