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SOD1-related ALS: what has it told us about motor neuron degeneration? - part 2
Published on May 30, 2022 34 min
Other Talks in the Series: ALS and Other Motor Neuron Disorders
Cognition in ALS and the overlap with frontotemporal dementia (FTD)
- Dr. Thomas Bak
- University of Edinburgh, UK
Let's now think about the mechanisms of motor neuron injury when a patient has a change in one amino acid in that SOD1 protein.
What we've learned over the last period of years really, is that the process of motor neuron injury is complex. At least 11 different things go wrong in the presence of mutant SOD1 in the motor neuron cells but also in the surrounding glial cells. There's oxidative stress, inflammatory cascades, cytotoxicity, so excessive activation of glutamate receptors, mitochondrial dysfunction, protein aggregation, impaired protein homeostasis, as I showed you before, impaired DNA repair, dysregulated cleocytoplasmic transport, abnormalities of RNA processing, dysregulation of vesicle transport, dysregulated axonal transport, and really importantly, it's not just the motor neurons but it's the "neighbourhood" cells as well that develop abnormal features. It is quite a complex process by which that motor neuron damage happens.
What we've learnt by studying mutant SOD1, it is not a loss of function of that protein that causes the disease. In the presence of a mutation, the SOD1 protein develops a toxic gain of function. That has been shown very clearly with the transgenic mouse models and genetic engineering in mice. If you put in the human SOD1 mutation, the mice develop ALS. But if you knock out the SOD1 genes, so a complete loss of function of the mouse SOD1, they do not develop ALS/MND. It's a toxic gain of function, not a loss of function. This slide just explains that this protein toxicity,