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

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.