Calcineurin Activation by Prion Protein Induces Neurotoxicity via Mitochondrial Reactive Oxygen Species

Abstract

Prion diseases are caused by PrPsc accumulation in the brain, which triggers dysfunctional mitochondrial injury and reactive oxygen species (ROS) generation in neurons. Recent studies on prion diseases suggest that endoplasmic reticulum (ER) stress induced by misfolding proteins such as misfolded prion protein results in activation of calcineurin. Calcineurin is a calcium-related protein phosphatase of type 2B that exists in copious quantities in the brain and acts as a critical nodal component in the control of cellular functions. To investigate the relationship between calcineurin and intracellular ROS, we assessed the alteration of CaN and ROS induced by prion peptide (PrP) 106-126. Human prion peptide increased mitochondrial ROS by activating calcineurin, and the inhibition of calcineurin activity protected mitochondrial function and neuronal apoptosis in neuronal cells. These results suggest that calcineurin plays a pivotal role in neuronal apoptosis by mediating mitochondrial injury and ROS in prion diseases.

Αnti-prion effects of anthocyanins

“…Conversely, reduced ROS levels are associated with increased survival and improved phenotype [ 22 ]. Furthermore, PrP Sc aggregation causes an uptake in mitochondrial ROS production and decreased levels of oxidative phosphorylation (OXPHOS) [ [27] , [28] , [29] ], which further aggravates ROS formation and oxidative stress observed in prion-affected cells [ 23 , 30 ].…”

Calcineurin Controls Cellular Prion Protein Expression in Mouse Astrocytes

“…CaN acts through both direct protein dephosphorylation and activation of gene transcription, e.g., through the direct activation of transcription factors of activated T-cells (NFAT) [ 10 , 19 , 20 ]. Over-activation of CaN plays a pivotal role in reactive gliosis and neuroinflammation in Alzheimer’s disease (AD) [ 10 , 11 , 20 , 21 , 22 , 23 , 24 ]. A preclinical alteration of CaN has been reported in the TgPG14 mouse model of inherited prion disease [ 25 , 26 ], and treatment of prion-infected mice with the CaN inhibitor FK506 delays disease onset and promotes PrP degradation [ 27 , 28 , 29 ].…”

New Therapeutic Approaches against Inflammation and Oxidative Stress in Neurodegeneration

“…In the experimental study conducted by Moon et al, calcineurin, a calcium-related protein phosphatase of type 2B expressed in the brain, was found to act as a critical checkpoint in the prion-dependent control of different cellular functions [ 16 ]. PrPsc can accumulate in the brain in pathological conditions and induce mitochondrial dysfunctions and reactive oxygen species (ROS) generation in neurons [ 17 ].…”