Investigation of Endogenous Retroviruses in the Pathogenesis of Sporadic Amyotrophic Lateral Sclerosis (ALS) by

Day, Edmund 2022. Investigation of Endogenous Retroviruses in the Pathogenesis of Sporadic Amyotrophic Lateral Sclerosis (ALS) by. PhD thesis University of Westminster Life Sciences https://doi.org/10.34737/w121w

TitleInvestigation of Endogenous Retroviruses in the Pathogenesis of Sporadic Amyotrophic Lateral Sclerosis (ALS) by
TypePhD thesis
AuthorsDay, Edmund
Abstract

Human Endogenous Retroviruses (HERVs) are remnants of ancient retroviral infections that have become incorporated into the human genome over the course of our evolution as a species. These fossil viruses have been co-opted by our genome as regulators of cellular gene expression amongst various other functions. Over the past few years however they have been increasingly discovered as differentially expressed in neurological conditions such as Amyotrophic Lateral Sclerosis.

While HERV-K (HML-2) transcripts were reported as elevated in premotor cortex samples from an ALS American cohort by Li et.al. (2015) the RT-qPCR assays performed in this sudy, using the same primers and reaction conditions in a larger ALS UK cohort were unable to corroborate these findings. Our collaborators at Kings College London, however, were able to find a novel HERV-K3 (HML-6) transcript on locus 3p21.31c upregulated in the primary motor cortex. We were able to confirm this using a subset of their primary motor cortex samples using RT-qPCR primers but were unable to replicate the results in a larger premotor cortex cohort. Using the modified ERVMap RNA-Seq method used by Jones et.al. (2021) we were able to analyse a number of publicly available datasets covering Cerebellum, Frontal Cortex, Motor Cortex and Peripheral Blood Mononuclear Cells. Within these datasets a number of novel HERVs were identified as being differentially expressed across the tissue types. A single HERV-H transcript was seen to be significantly downregulated in both the frontal cortex by RNA-Seq analysis and in the premotor cortex of our ALS UK cohort.

This identification of a novel HERV-H transcript being differentially regulated in the premotor cortex and subsequent RNA-Seq analysis on the blood and the brain provides a solid basis for future research into HERVs as novel biomarkers for ALS in which a diagnostic marker for early diagnosis and target for treatment is lacking to-date.

Year2022
File
File Access Level
Open (open metadata and files)
PublisherUniversity of Westminster
Publication dates
PublishedAug 2022
Digital Object Identifier (DOI)https://doi.org/10.34737/w121w

Related outputs

Response to the Letter from Garcia-Montojo and colleagues concerning our paper entitled, Quantitative analysis of human endogenous retrovirus-K transcripts in postmortem premotor cortex fails to confirm elevated expression of HERV-K RNA in amyotrophic lateral sclerosis.
Garson, J.A., Usher, L., Al-Chalabi, A., Huggett, J., Day, E. and McCormick, A.L. 2019. Response to the Letter from Garcia-Montojo and colleagues concerning our paper entitled, Quantitative analysis of human endogenous retrovirus-K transcripts in postmortem premotor cortex fails to confirm elevated expression of HERV-K RNA in amyotrophic lateral sclerosis. Acta Neuropathologica Communications. 7 102. https://doi.org/10.1186/s40478-019-0756-9

Quantitative analysis of Human Endogenous Retrovirus-K transcripts in postmortem premotor cortex fails to confirm elevated expression of HERV-K RNA in amyotrophic lateral sclerosis
Garson, J.A., Usher, L., Al-Chalabi, A., Huggett, J., Day, E.F. and McCormick, A.L. 2019. Quantitative analysis of Human Endogenous Retrovirus-K transcripts in postmortem premotor cortex fails to confirm elevated expression of HERV-K RNA in amyotrophic lateral sclerosis. Acta Neuropathologica Communications. 7 45. https://doi.org/10.1186/s40478-019-0698-2

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