Oxidative and Inflammatory Events in Prion Diseases: Can They Be Therapeutic Targets?

Abstract

Prion diseases are a group of incurable infectious terminal neurodegenerative diseases caused by the aggregated misfolded PrPsc in selected mammals including humans. The complex physical interaction between normal prion protein PrPc and infectious PrPsc causes conformational change from the α- helix structure of PrPc to the β-sheet structure of PrPsc, and this process is repeated. Increased oxidative stress is one of the factors that facilitate the conversion of PrPc to PrPsc. This overview presents evidence to show that increased oxidative stress and inflammation are involved in the progression of this disease. Evidence is given for the participation of redoxsensitive metals Cu and Fe with PrPsc inducing oxidative stress by disturbing the homeostasis of these metals. The fact that some antioxidants block the toxicity of misfolded PrPc peptide supports the role of oxidative stress in prion disease. After exogenous infection in mice, PrPsc enters the follicular dendritic cells where PrPsc replicates before neuroinvasion where they continue to replicate and cause inflammation leading to neurodegeneration. Therefore, reducing levels of oxidative stress and inflammation may decrease the rate of the progression of this disease. It may be an important order to reduce oxidative stress and inflammation at the same time. This may be achieved by increasing the levels of antioxidant enzymes by activating the Nrf2 pathway together with simultaneous administration of dietary and endogenous antioxidants. It is proposed that a mixture of micronutrients could enable these concurrent events thereby reducing the progression of human prion disease.

Role of Nuclear Factor Kappa B (NF-κB) Signalling in Neurodegenerative Diseases: An Mechanistic Approach

“…The activation of transcriptional factor (NF-KB) enhances the apoptotic neuronal death by elevating the expression of many pro-apoptotic genes for certain proteins (p53, BcL-Xs, BAX, Fas ligand), thereby releasing cytochrome C undergoing mitochondrial dysfunction and endoplasmic stress further releasing calcium activating Bad (pro-apoptotic protein). The up-regulation of cytokines IL-1 & TNF-alpha at the site of synaptic damage causes reactive oxygen species such as hydrogen peroxide, resulting in excitotoxicity and neurodegeneration [ 103 , 108 - 110 ].…”

Yeast Models for Amyloids and Prions: Environmental Modulation and Drug Discovery

“…The early-life environment was implicated as one of primary factors in defining an individual’s susceptibility to AD and PD [61,62,63]. Fundamental aging-related processes, such as decreased adaptation to stress and accumulation of reactive oxygen species (ROS), as well as a decline in protein homeostasis, may serve as initiators of Aβ and prion aggregation [64,65,66]. The current model of AD considers amyloid formation by Aβ as a triggering factor in AD [67].…”

microRNA-146a-5p, Neurotropic Viral Infection and Prion Disease (PrD)

“…The misfolded, abnormal and insoluble isoform of PrPc known as PrPsc self-associates into pro-inflammatory, protease-resistant aggregates that are insoluble in most detergents and chaotropic agents [59,75,84,[89][90][91]. The molecular mechanisms of PrPsc neurotoxicity that drive the initiation, development and progression of PrD are highly complex and, similar to the case of AD, increased oxidative stress and chronic inflammation appear to be critically involved in the initiation and progression of PrD [5,73,86,[92][93][94][95]. Typically, activated microglia accumulate within the immediate vicinity of abnormal PrPsc aggregates, and they release cytokines such as IL-1β that play important roles in the inflammatory pathogenesis of PrD, including the upregulation of genes that promote pro-inflammatory signaling and innate-immune system deficits [86,90].…”