an ALS Hypothesis

John H. johnhkm at netsprintXXXX.net.au
Tue Feb 1 06:04:24 EST 2000

Thanks Dag and Austin,

I remembered the article so will cite it here (good read for me):

"Sealing one's fate: control of cell death in neurons"
Louise Bergeron and Junying Yuan

Current Opinion in Neurobiology 1998, 8:55-63

p 60
In humans, ALS is characterized by the progressive loss of motor neurons int
he brain stem and spinal cord [ain't that great news Ken], leading to muscle
weakness and atrophy followed by paralysis and death. While most cases are
sporadic, 5-10% are familial (FALS). A breakthrough came ... SOD1. ...
Kostic et al crossed transgenic mice overexpressing BCL-2 neurons with mice
carrying the FALS SOD1 mutation. BCL-2 was effective at delaying the onset
of the disease, thus increasing lifespan of themice by about 19%; however,
once symptoms appeared, progression to paralysis and death remained
unchanged. BCL-2 delayed both the loss of motor neurons and theincrease in
expression oftyhe early markers of cell injury, c-Jun and ubiquitin. ... "

BCL-2 can useful in delaying apoptosis in other pathologies also. A paper I
read recently suggested that the p53 gene may regulate apoptosis via the
BCL-2\BAX etc ratios. So I'm not sure how significant this BCL-2 delay is,
except for the possibility that mitachondrial membrane permeability or
dysfunction is probably involved. Once cytochrome c and AIF are away in the
cytoplasm and the caspase cascade is away I think cell death is inevitable.

Perhaps BCL-2, at least in motor neurons, is particularly sensitive to some
type of oxidative stress.
I need to brush up, find out if oxidative stress alone can activate
procapase 9. Haven't even looked at motor neurons though.

Little by little,

John H.

Austin P. So (Hae-Jin) <haejin at netinfo.ubc.caX> wrote in message
news:3895CA2F.2A802315 at netinfo.ubc.caX...
> Familial ALS has been linked to SOD mutations....but that accounts for <
5% of
> all ALS cases, so in fact the field is still very wide open.
> So...mitochondrial dysfunction is a good candidate, as is an autoimmune
> (Llinas touted this for a while before the FALS/SOD link was
> against the P-type channel). People have speculated on a glutamate
> source....but again nothing concrete.
> "John H." wrote:
> > I thought it may have been a SOD problem, but haven't managed to have a
> > close look at it yet. Isn't there a familial tendency here also?
> >
> > Would someone more knowledgeable than the current authors in this thread
> > care to enlighten? I know something about apoptosis etc but ALS .... .
> --
> ---
> Austin P. So (Hae Jin)
> I.I.S.G.P.
> Biotechnology Laboratory
> University of British Columbia
> E-mail: haejin at netinfo.ubc.ca
> http://www.interchange.ubc.ca/haejin/index.html (under construction)

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