Effect of siRNA-induced silencing of cellular prion protein on tyrosine hydroxylase expression in the substantia nigra of a rat model of Parkinson’s disease

Abstract

ABSTRACT. The most significant pathological feature of Parkinson's disease (PD) is the progressive degeneration of dopaminergic (DA) neurons in the substantia nigra. Currently, available treatments for PD cannot prevent the loss of DA neurons. Tyrosine hydroxylase (TH) expressed in substantia nigra neurons catalyzes the conversion of tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA), which is the rate-limiting step of DA biosynthesis. Major reasons for PD occurrence include decreased TH activity in the substantia nigra and secondary DA suppression. Decreased TH activity and the resulting suppression of DA synthesis (or neurotransmission) in the substantia nigra are key factors underlying the development of PD. Cellular prion protein (PRP) is a membrane glycoprotein expressed in the central nervous system. Although the sequence of PRP is highly conserved, its physiological function is unclear. The purpose of this study was to investigate the effect of PRP-targeted small interfering RNA (siRNA) on TH expression in a rat model of PD. Thirty male Wistar rats were injected with 6-hydroxydopamine (6-OHDA) to generate a model of PD. The rats then received injections of PRP-siRNA or nonsense siRNA in the lateral ventricles. Substantia nigra samples were collected for quantification of PRP and TH expression using real-time polymerase chain reaction and western blotting. PRP-siRNA decreased PRP expression in the substantia nigra. TH expression was decreased in PD model rats but was increased after PRP silencing. We conclude that PRP-siRNA may increase TH expression in vivo and may therefore exert protective effects on neurons in a model of PD.

Expression of prion protein in the cerebrospinal fluid of patients with Parkinson’s disease complicated with rapid eye movement sleep behavior disorder

“…PrP expression in CSF should be detected in a larger number of PD patients, and the impact on the PD model of overexpression of PrP or deletion of PrP also requires further investigation. Exciting results have illustrated the effect of PrP on PD in a rat model via siRNA silencing of cellular prion protein (Wang et al, 2016). Further studies could utilize similar gene-editing tools to elucidate the potential of CSF PrP in the clinical diagnosis of PD and PD with RBD.…”

NF‑κB is negatively associated with Nurr1 to reduce the inflammatory response in Parkinson's disease

“…Studies have shown that the occurrence and development of Pd are related to the environment, genetics, metabolic deficiency, oxidative stress and neuroinflammatory response (2,7,8). reportedly, inhibition of tyrosine hydroxylase (TH) activity was found to be closely related to the occurrence of Pd, and immunohistochemical determination of TH expression has provided an essential tool for visualization and quantification of the damage and loss to dopaminergic neurons in Pd models (9,10). additionally, an in vitro study by Salemme et al (11) indicated that dihydroasparagusic acid can alleviate neurodegenerative diseases by inhibiting inflammatory and oxidative processes.…”

Towards chronic deep brain stimulation in freely moving hemiparkinsonian rats: applicability and functionality of a fully implantable stimulation system

“…Animal models are essential in experimental medical science to investigate etiology, mechanisms and symptoms of human diseases as well as new potential therapeutic strategies. For PD, the 6-hydroxydopamine (6-OHDA) rat model has proven to be a valuable tool in understanding the underlying mechanisms of the disease and in the establishment of new therapies [16][17][18][19][20]. It belongs to the toxin-induced models and is based on the uni-or bilateral intracerebral injection of 6-OHDA into the medial forebrain bundle, the substantia nigra pars compacta, or subregions of the caudate-putamen complex.…”