Projects per year
Abstract
The development of therapies to combat neurodegenerative diseases is widely recognized as a research priority. Despite recent advances in understanding their molecular basis, there is a lack of suitable early biomarkers to test selected compounds and accelerate their translation to clinical trials. We have investigated the utility of in vivo reporters of cytoprotective pathways (e.g. NRF2, p53) as surrogate early biomarkers of the ALS degenerative disease progression. We hypothesized that cellular stress observed in a model of ALS may precede overt cellular damage and could activate our cytoprotective pathway reporters. To test this hypothesis, we generated novel ALS-reporter mice by crossing the hTDP-43tg model into our oxidative stress/inflammation (Hmox1; NRF2 pathway) and DNA damage (p21; p53 pathway) stress reporter models. Histological analysis of reporter expression in a homozygous hTDP-43tg background demonstrated a time-dependent and tissue-specific activation of the reporters in tissues directly associated with ALS, before moderate clinical signs are observed. Further work is warranted to determine the specific mechanisms by which TDP-43 accumulation leads to reporter activation and whether therapeutic intervention modulates reporters' expression. We anticipate the reporter strategy could be of great value in developing treatments for a range of degenerative disorders.
Original language | English |
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Article number | 240073 |
Number of pages | 7 |
Journal | Open Biology |
Volume | 14 |
Issue number | 10 |
Early online date | 30 Oct 2024 |
DOIs | |
Publication status | Published - Oct 2024 |
Keywords
- Amyotrophic Lateral Sclerosis/metabolism
- Animals
- Mice
- DNA-Binding Proteins/metabolism
- Disease Models, Animal
- Humans
- Mice, Transgenic
- Genes, Reporter
- Oxidative Stress/drug effects
- NF-E2-Related Factor 2/metabolism
- Drug Development
- DNA Damage
- Biomarkers
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Dive into the research topics of 'Novel in vivo TDP-43 stress reporter models to accelerate drug development in ALS'. Together they form a unique fingerprint.Projects
- 3 Finished
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Preclinical Models to Accelerate Drug Discovery in ALS/FTLD
Henstridge, C. (Investigator) & Inesta-Vaquera, F. (Investigator)
1/11/21 → 31/12/23
Project: Research
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Preclinical Models To Accelerate Drug Discovery In ALS/FTLD
Henstridge, C. (Investigator) & Inesta-Vaquera, F. (Investigator)
1/11/21 → 31/12/23
Project: Research
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High Resolution Imaging of Cortical Synaptic Integrity in Motor Neurone Disease
Henstridge, C. (Investigator)
1/05/19 → 31/08/23
Project: Research