190 Prion Protein Knockout Leads to Differential RNA Expression Following Head Injury

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INTRODUCTION: It is not well understood why repetitive head injury causes the behavioral and pathologic sequelae associated with Chronic Traumatic Encephalopathy. Cellular prion protein (PrPC) is associated with several neurodegenerative diseases including Alzheimer’s disease and Creutzfeldt-Jakob disease and we have previously demonstrated that PrPC is required for the pathology and behavior associated with CTE after TBI. We show that Prpc knockout leads to differential mice cortex gene expression in a murine repetitive head injury model. METHODS: Experimental groups consisted of PrPC-knockout (Prnp-/-) and PrPC wild type (WT) mice. Bilateral close head injury consisted of daily impactions over 10 days with appropriate unimpacted control. All animals were allowed to recover for 6 weeks. Mice were sacrificed and brain cortexes rapidly dissected and flash frozen for RNA extraction, sequencing, and quantification. RESULTS: We identified 52 upregulated and 134 downregulated genes in WT impacted compared to unimpacted WT mice. 301 genes were upregulated and 85 downregulated in Prnp-/- impacted mice compared to Prnp-/- mice without impactions. We identified 85 upregulated and 86 downregulated genes in Prnp-/- impacted mice compared to WT impacted mice. RNA expression of KLK6 is upregulated by a factor of 2.3 and KChip3 is downregulated by a factor of 1.3 in Prnp-/- impacted mice compared to WT impacted mice. CONCLUSIONS: Deletion of PrPc in a murine model of CTE leads to differential expression of multiple gene clusters. Deletion of Prpc in impacted mice upregulates KLK6 and downregulates KCHip3 which have been implicated in neurodegenerative processes and neuroinflammation including Alzheimer’s disease. We have previously demonstrated that Prpc is required for cognitive deficits and standard histologic pathology following head injury who's biochemical mechanism may implicate KLK6 and KCHip3.