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,
