Transcriptional signature of prion-induced neurotoxicity in a Drosophila model of transmissible mammalian prion disease.

Transcriptional signature of prion-induced neurotoxicity in a Drosophila model of transmissible mammalian prion disease. Biochem J. 2020 Feb 28;477(4):833-852 Authors: Thackray AM, Lam B, Shahira Binti Ab Razak A, Yeo G, Bujdoso R Abstract Prion diseases are fatal transmissible neurodegenerative conditions of humans and animals that arise through neurotoxicity induced by PrP misfolding. The cellular and molecular mechanisms of prion-induced neurotoxicity remain undefined. Understanding these processes will underpin therapeutic and control strategies for human and animal prion diseases, respectively. Prion diseases are difficult to study in their natural hosts and require the use of tractable animal models. Here we used RNA-Seq-based transcriptome analysis of prion-exposed Drosophila to probe the mechanism of prion-induced neurotoxicity. Adult Drosophila transgenic for pan neuronal expression of ovine PrP targeted to the plasma membrane exhibit a neurotoxic phenotype evidenced by decreased locomotor activity after exposure to ovine prions at the larval stage. Pathway analysis and quantitative PCR of genes differentially expressed in prion-infected Drosophila revealed up-regulation of cell cycle activity and DNA damage response, followed by down-regulation of eIF2 and mTOR signalling. Mitochondrial dysfunction was identified as the principal toxicity pathway in prion-exposed PrP transgenic Drosophila. The transcriptomic changes we obse...
Source: The Biochemical Journal - Category: Biochemistry Authors: Tags: Biochem J Source Type: research