Functional Genomics Approach for Identification of Molecular Processes Underlying Neurodegenerative Disorders in Prion Diseases

Abstract

Prion diseases or transmissible spongiform encephalopathies (TSEs) are infectious neurodegenerative disorders leading to death. These include Cresutzfeldt-Jakob disease (CJD), familial, sporadic and variant CJD and kuru in humans; and animal TSEs include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease (CWD) of mule deer and elk, and transmissible mink encephalopathy. All these TSEs share common pathological features such as accumulation of mis-folded prion proteins in the central nervous system leading to cellular dysfunction and cell death. It is important to characterize the molecular pathways and events leading to prion induced neurodegeneration. Here we discuss the impact of the functional genomics approaches including microarrays, subtractive hybridization and microRNA profiling in elucidating transcriptional cascades at different stages of disease. Many of these transcriptional changes have been observed in multiple neurodegenerative diseases which may aid in identification of biomarkers for disease. A comprehensive characterization of expression profiles implicated in neurodegenerative disorders will undoubtedly advance our understanding on neuropathology and dysfunction during prion disease and other neurodegenerative disorders. We also present an outlook on the future work which may focus on analysis of structural genetic variation, genome and transcriptome sequencing using next generation sequencing with an integrated approach on animal and human TSE related studies.

Gene expression profiling of brains from bovine spongiform encephalopathy (BSE)-infected cynomolgus macaques

“…TSEs include Creutzfeldt-Jakob Disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), kuru and fatal familial insomnia (FFI) in humans [2], bovine spongiform encephalopathy (BSE) in cattle [3], scrapie in sheep and goats [4], chronic wasting disease (CWD) in cervids [5], transmissible mink encephalopathy, and feline spongiform encephalopathy (FSE) [6]. …”

Application of “Omics” Technologies for Diagnosis and Pathogenesis of Neurological Infections

“…While prion agents cannot be subjected to NGS studies for the detection of pathogen because the encoding nucleic acids are host-derived, numerous host transcriptomic studies have been performed to investigate gene expression alterations following prion infections (reviewed in [55]). Similar to viral infections of the nervous system, transcriptional profiling has been employed chiefly to gain insights into the pathogenic mechanisms that lead to neurodegeneration during prion infection.…”

Microdissection and transcriptional profiling

“…12). Similar transcriptional profiles have been detected within other animal models, such as BSE-infected cattle (reviewed in ref.…”

“…Similar transcriptional profiles have been detected within other animal models, such as BSE-infected cattle (reviewed in ref. 12) as well as in human sporadic Creutzfeldt-Jakob disease patients. 13 Although further discussion of these studies is beyond the scope of this review, the molecular responses detected in these samples mirror that of the mouse prion models and further supports the utilization of the mouse models for studying the neurodegenerative process that is also observed in larger animals and human patients afflicted with prion disease.…”