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Printable Handouts
Navigable Slide Index
- Introduction
- Lecture outline (4)
- Complex pathophysiological mechanisms in MND: lessons from SOD1
- Toxic gain of function of SOD1mut drives motor neuron injury
- Protein aggregates are a common feature of neurodegenerative diseases
- Many forms of SOD1mut have a propensity to form aggregates and inclusions
- SOD1mut protein maturation
- Large variability in aggregation propensity across SOD1 mutations
- Glutamate-mediated excitotoxicity
- Mitochondrial dysfunction in mutant SOD1 G93A mice
- How does mutant SOD1 exert a neurotoxic effect through mitochondria?
- The non-neuronal cell “neighbourhood” contribution to motor neuron injury
- Evidence for a role of non-neuronal cells in ALS/MND
- Astrocytes contribute to ALS pathogenesis
- Different cell types participate in different mechanisms
- Prion-like propagation hypothesis
- SOD1 acts as a redox-sensitive nuclear transcription factor
- Lecture outline (5)
- Prognostic heterogeneity: fast and slow progressors
- Prognostic heterogeneity
- Differences in the motor neuron transcriptome in fast vs. slow progressing SOD1 mouse models
- NRF2 mRNA and protein levels in the two mouse strains at disease onset
- Lecture outline (6)
- Failed translation from the SOD1 mouse model
- Multiple mechanisms contribute to MN injury in ALS: lessons from SOD1
- Protein folding therapeutic target
- A phase 2, randomised, placebo-controlled trial of arimoclomol in amyotrophic lateral sclerosis
- Multiple mechanisms contribute to MN injury in ALS: lessons from SOD1
- SOD1 silencing in SOD1G93A transgenic mouse model
- This approach would be difficult to apply to humans
- Promising new viral vectors: scAAV9
- New SOD1 knock-down studies in mice using AAV9 viral vectors
- Cisterna magna: P1 study
- SOD1 protein levels reduced in the nervous system
- SOD1 protein levels reduced in the cerebrospinal fluid
- No significant off-target effects from knock-down of SOD1
- Biogen SOD1 antisense-oligonucleotide (ASO) phase 1 trial (1)
- Biogen SOD1 antisense-oligonucleotide (ASO) phase 1 trial (2)
- Timeline of discoveries for SOD1-MND
- Conclusions
- Acknowledgements: research funding agencies
Topics Covered
- Mechanisms of motor neuron injury in the presence of SOD1 mutations
- glutamate-mediated excitotoxicity
- Determinants of fast and slow disease progression
- Therapeutic approaches including gene therapy
Links
Series:
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Therapeutic Areas:
Talk Citation
Shaw, P. (2022, May 30). SOD1-related ALS: what has it told us about motor neuron degeneration? - part 2 [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved December 3, 2024, from https://doi.org/10.69645/JPZA9910.Export Citation (RIS)
Publication History
Financial Disclosures
- Prof. Dame Pamela Shaw has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
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
Transcript
Please wait while the transcript is being prepared...
0:03
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.
0:17
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.
1:31
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,
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