Investigating pathological mechanisms in the Thy1-hTDP43 ALS mouse model

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease caused by the death of both upper and lower motor neuron populations, which are responsible for initiating and controlling movement. ALS is a complex and heterogeneous disease, with only 10% of cases arising from an inherited genetic mutation. Although over 40 genes have been linked to ALS pathology, the cause of disease is still unknown for the vast majority of patients, and treatment options remain limited. Multiple pathological mechanisms are subsequentially activated in ALS, making the development of therapeutic options diAicult. The activation of these pathways does seem to have a common link, causing the generation of cellular stress. The generation of cellular stress induces the activation of many protective mechanisms, such as the formation of stress granules (SGs). SGs are typically transient structures that sequester translationally-stalled mRNA, RNA-binding proteins, ribosomal components, and translation initiation factors to promote cell survival upon stress induction. In ALS and other neurodegenerative diseases, SGs are, however, hypothesised to play pathological roles, with changes in SG composition and morphology observed in ALS models. SGs in ALS are further seen to colocalise with ALS-associated proteins in patient tissues, hinting at a causative role in disease pathogenesis. SGs have only been investigated in ALS using an external stressor. As SGs are dynamic structures, their composition and morphology have been seen to change depending on the external stressor. Therefore, we sought to investigate the role of SG formation and related mechanisms for the first time in vivo without the use of an external stressor using the Thy1-hTDP-43 mouse model. At the late symptomatic disease stage, we found a significant upregulation of SG formation in spinal motor neurons, significant upregulation of SG formation markers in both brain and spinal cord tissue at both the protein level and the transcription level in Tg/Tg mice. These SGs were seen to colocalise with an ALSassociated protein, TDP43, in spinal motor neurons, implying a pathological role for their formation. Additionally, key factors suppressed by protective SG formation were upregulated ROS and NLRP3, indicating altered SG function in ALS. Pathological stress granules are typically broken down by autophagy degradation. Autophagy degradation was unchanged at the time of SG upregulation and significantly decreased at later time points, implying a defective clearance of SGs in the hTDP43 mouse model. As SG formation can occur from several diAerent cellular stress response pathways, we next wanted to explore potential upstream causes of SG formation in ALS. We saw a significant upregulation of inflammation and oxidative stress at the late symptomatic stage, implicating these as possible SG-activating mechanisms. This work identifies a novel pathway that is dysfunctional during ALS disease progression that could present a possible target for future therapeutic options.

Grantor dc:publisher

The University of Edinburgh

Year dc:date.issued

2025

Author dc:creator

• Ridgway, Zara Lilly

Advisors dc:contributor.advisor

• Gillingwater, Tom
• Chaytow, Helena

• Thy1-hTDP43 ALS mouse model
• Amyotrophic Lateral Sclerosis
• stress granules

Language dc:language.iso

en

Identifier URI

http://dx.doi.org/10.7488/era/5566

OAI identifier oai:identifier

oai:era.ed.ac.uk:1842/43018