TRPV4 contributes to ER stress and inflammation: implications for Parkinson’s disease

Abstract

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 Ca2+ 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 Ca2+-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.

Lipopolysaccharide-Induced Model of Neuroinflammation: Mechanisms of Action, Research Application and Future Directions for Its Use

“…However, the influence of TRPV4 on inflammation tends to be clearer. To the date, it is established that the activation of TRPV4 exacerbates inflammatory responses and triggers neuroinflammation, while TRPV4 inhibitors exert a neuroprotective effect [ 53 , 54 ]. TRPV4 is a nonselective Ca 2+ channel, and its activation results in an increased intracellular Ca 2+ concentration and increased iNOS activity, which leads to the production of pro-inflammatory mediators, such as eicosanoids [ 55 ].…”

Electroacupuncture ameliorates neuroinflammation by inhibiting TRPV4 channel in ischemic stroke

“…Studies have revealed the use of TRPV4 antagonists can significantly reduce the occurrence of neuroinflammation in diseases such as Parkinson's disease or depression. 29,30 An F I G U R E 5 Inhibition of TRPV4 may contribute to the effects of EA on ameliorating the neurological functional deficits in MCAO mice. (A) On the first and third day after MCAO, both GSK219 and GSK219 + EA reduced the neurological deficit scores in MCAO mice, and there was no statistically significant difference between the two groups.…”

Cadmium Transforms Astrocytes into the A1 Subtype via Inducing Gap Junction Protein Connexin 43 into the Nucleus

“…This stain has been widely used to identify damaged neurons. 37 The number of Nissl bodies would decrease once neurons are damaged. 38 Therefore, it is reliable to preliminarily judge that neurons have been damaged and behavior disorder through the structural changes of Nissl bodies and reduction of DRD2 protein (Figure 1).…”

“…The Nissl body is a marker of the functional state of neurons and was detected in the cytoplasm and dendrites of neurons. This stain has been widely used to identify damaged neurons . The number of Nissl bodies would decrease once neurons are damaged .…”