Author: Megan Fowler
Fowler, Megan, 2024 Endogenous retroviruses and the association with TDP-43 and inflammation in the cause and progression of Motor Neuron Disease, Flinders University, College of Medicine and Public Health
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Motor Neuron Disease (MND), also known as amyotrophic lateral sclerosis (ALS) is a progressive neurological disorder characterised by the death of upper and lower motor neurons. The aetiology of MND remains unknown and treatment options are limited. A hallmark of MND pathology is altered localisation of the transactive response (TAR) DNA binding protein 43 kDa (TDP-43), which is normally found within the nucleus of neuronal and glial cells and is involved in RNA regulation. In MND, TDP-43 aggregates within the cytoplasm and facilitates motor neuron degeneration.
The exact mechanism of how TDP-43 mislocalisation results in neurodegeneration is still unclear. One proposed mechanism involves endogenous retroviruses (ERVs). ERVs are genomic remnants of ancient viral infection events, with most being inactive and not retaining the capacity to encode a fully infectious virus. However, some ERVs retain the ability to be activated and transcribed, and ERV transcripts have been found to be elevated within the brain tissue of MND patients. Therefore, ERVs, specifically human endogenous retrovirus type K (HERV-K), have been proposed to be involved in the cause and propagation of neurodegeneration.
Due to the association between ERVs and their potential role in neurodegeneration, antiretroviral therapy to target ERVs was proposed as a treatment. A phase II clinical trial of an antiretroviral therapy, Triumeq, showed promising results for reducing HERV-K levels in a small cohort of MND patients. While this a promising result for identification of a novel therapy for MND, further research into this treatment is needed.
The aim of the current study was to test the efficacy of Triumeq in a TDP-43 mouse model of MND to further elucidate the mechanisms of action of Triumeq in MND. The study first assessed the tolerability of Triumeq in a small cohort of TDP-43 transgenic mice where it was deemed tolerable before testing in a larger cohort. The mice studies identified a significant improvement in motor performance in TDP-43 mice treated with Triumeq. However, this significant difference was only seen at Day 17 of the study and no further differences were observed by the time the mice reached the ethical end point. This difference in motor performance also coincided with a significantly lower level of urinary p75ECD in the treated mice. At this same point of disease, there was also a significantly lower number of motor neurons in the lumbar region of untreated mice compared to treated mice. Other disease progression measures including weight loss were not significantly different between Triumeq-treated mice and untreated mice at any point of the study. Real Time Quantitative Polymerase Chain Reaction (RT-qPCR) was employed to measure the mRNA expression of inflammatory markers within the brain of the treated and untreated mice. While there were no significant differences in expression between treatment groups, there was a correlation between TDP-43 expression and an inflammatory cytokine C-X-C motif chemokine ligand 10 (CXCL10), a chemokine known to be increased in MND patients with influence on neurodegenerative mechanisms.
Based on the results from Chapter 3, an increased dose of Triumeq was tested in the mice to determine any further therapeutic benefit. While only a small cohort was used for this study, no significant differences between mice treated with an increased dose of Triumeq and untreated mice were observed for any measure of disease progression. These findings, alongside the findings from Chapter 3, suggest that Triumeq could be reducing neurodegenerative mechanisms at the current dose used in the human clinical trials.
In addition to the mice studies, this study also aimed to further elucidate the mechanism of Triumeq on TDP-43 and HERV-K relationship in vitro. To do this, the expression of HERV-K and TDP-43 in multiple cell lines, including a primary cell, was analysed. Using one of the analysed cell lines, exogenous viral infection was shown to increase the levels of HERV-K expression, independent of TDP-43 expression but associated with increased inflammatory cytokine expression.
This study provides valuable insight into the use of Triumeq as a treatment for MND and further elucidate the involvement of HERV-K in MND pathology, specifically involving TDP-43 and inflammatory pathways. Further elucidating the functional relationship between HERV-K, neuroinflammation and TDP-43 will allow for a greater understanding of potential therapeutics to target the intersection of these mechanisms and hopefully slow or halt MND disease progression.
Keywords: Motor Neuron Disease, MND, TDP-43, inflammation, Amyotrophic Lateral Sclerosis, ALS
Subject: Medicine thesis
Thesis type: Doctor of Philosophy
Completed: 2024
School: College of Medicine and Public Health
Supervisor: Mary-Louise Rogers