PrPC expression and calpain activity independently mediate the effects of closed head injury in mice

Publication date: 15 March 2018
Source:Behavioural Brain Research, Volume 340
Author(s): Richard Rubenstein, Kevin K. Wang, Allen Chiu, Natalia Grinkina, Deep R. Sharma, Sanjeev Agarwal, Fan Lin, Zhihui Yang
The normal cellular prion protein (PrP^C) is a sialoglycoprotein with a glycophosphatidylinositol anchor and expressed in highest levels within the CNS particularly at neuronal synapses. This membrane-bound protein is involved with many cell functions including cell signaling and neuroprotection.Calpains are calcium-activated cysteine proteases that typically undergo controlled activation. PrP^C is a calpain substrate and is neurotoxic if it undergoes aberrant processing with cytosol accumulation. Following traumatic brain injury (TBI), there is an abnormal influx of Ca⁺² and overactivation of calpains resulting in neuronal dysfunction and cell death. We investigated whether PrP^C expression and calpain activity have an effect on, or are affected by, TBI.PrP^C expression in the hippocampus, cortex and cerebellum of WT and Tga20 (PrP^C overexpression) mice were unchanged after closed head injury (CHI). Further, PrP^C in WT and Tga20 mice was resistant to TBI-induced calpain proteolysis.CHI-induced calpain activation resulted in breakdown products (BDPs) of αII-spectrin (SBDPs) and GFAP (GBDP-44K) in all brain regions and mouse lines. CHI caused significant increases in SBDP145, GFAP and GBDP-44K when compared to sham. With few exceptions, the calpain inhibitor, SNJ-1945, reduced SBDP145 and GBDP-44K levels. Behavioral studies suggested that PrP^C and calpain independently affect learning and memory. Overall, we conclude that: (i) there is SNJ-1945-sensitive calpain activation in both neuron and glial cells following CHI, (ii) closed head trauma is not affected by, nor does it have an influence on, PrP^C expression, and (iii) PrP^C expression plays a minor role, if any, in CHI-induced calpain activation in vivo.



http://ift.tt/2Bv4zKc