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 redox-sensitive 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.
Highlights
Prion diseases are a group of rare progressive incurable transmissible infectious neurodegenerative diseases caused by aggregated misfolded β-sheet of PrPsc protein in selected mammals including humans
ROS activate Nrf2 which dissociates itself from Kelch-like ECH associated protein 1 (Keap1)- CuI-Rbx1 complex and translocates in the nucleus where it heterodimerizes with a small Maf protein, binds with Antioxidant Response Elements (ARE) leading to increased expression of target genes coding for several cytoprotective enzymes including antioxidant enzymes [97,98,99]
Prion diseases are a group of transmissible incurable progressive fatal neurodegenerative diseases
Summary
Prion diseases are a group of rare progressive incurable transmissible infectious neurodegenerative diseases caused by aggregated misfolded β-sheet of PrPsc protein in selected mammals including humans. Evidence showing that increased oxidative stress and inflammation are involved in the progression of this disease is assembled This includes support for the interaction of redox-sensitive metals Cu and Fe with PrPc and PrPsc leading to disruption of normal intracellular homeostasis of the metals, resulting in increased oxidative stress. Animal prion diseases include Bovine Spongiform Encephalopathy (BSE), scrapie of sheep, and chronic wasting disease of deer and elk These can be transmitted to humans by consumption of infected meat. Sporadic CJD results from spontaneous conversion of PrPc to PrPsc in some carriers of a specific mutation that enhances this possiblitiy, rather than from PrPsc infection from external sources [17, 18] This transition which does not involve genetic changes may take place spontaneously especially with some variants of PrPc. Familial Creuztfeldt-Jacob Disease (fCJD) is found in a small population of Libyan Jews that have extensively interbred for centuries. Sporadic CJD occurs mostly in older individuals with rapid progression of dementia leading to death within a year, whereas variant vCJD is found in younger individuals with slower progression of the cognitive dysfunction [22, 23]
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