Project
Targeting oxidative stress and metabolic dysfunctionin amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and
fatal neurodegenerative disorder leading to the death of the patient
within three to five years after diagnosis. Oxidative stress and
dysregulated metabolism are both extensively linked to ALS. Given
the lack of efficient treatment possibilities for ALS, this project aims to
elucidate the therapeutic potential of modulating oxidative stress and
metabolic dysfunction in ALS. Therefore, we will target oxidative
stress by inducing metabolic reorientation via prolyl hydroxylase 1
(PHD1) inhibition. PHD1 is an oxygen and metabolite sensor that
rewires energy metabolism. The role and therapeutic potential of
selective PHD1 ablation in ALS are unexplored. We aim to
investigate the effect of PHD1 ablation on ALS disease progression
in different ALS mouse models using genetic approaches and PHD1
antisense oligonucleotides. Single-cell transcriptomics will be
performed to explore the origin of the potential beneficial effects of
PHD1 ablation. Furthermore, we will use state-of-the-art
technologies, such as metabolomics and axonal tracing, in ALS mice
and patient-derived motor neurons to explore the mechanism of
action. This project offers an elegant way to study the role and
therapeutic potential of oxidative stress and energy metabolism using
highly innovative tools which could lead to ground-breaking findings
within the ALS field.