an ALS Hypothesis

kenneth Collins kpaulc at earthlink.net
Tue Feb 1 22:38:07 EST 2000

hi, John.

John H. wrote:
> 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], 

yes, thanks for posting this stuff.

>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. ... "

from the perspect of the hypothesis i've been discussing, i expect that
what the adminstered agents are doing is augmenting the neurons'
abilities to cope with 'excito-toxic' conditions that're generated by
the decrease of type II synchronization.

what's actually needed is a tracking-doen of the 'lesion' through which
the interminable TD E/I(up) condition is being interjected into the
supersystem, and fixing things at the 'lesion' site.

of course, if, contrry to the hypothesis i've been discussing, the
'lesion' is, in fact, a genetic 'lesion' that's distributed theougout
the supersystem, then it seems that the only way to possibly attack the
'lesion' would be through globally-distributed chemo approach, with
respect to which, i'm out of my depth.

it's just that it doesn't seem to be globally-distributed because
sensory fx is unaffected. and, on the motor side, things are obviously
'chained', with both feedback and feed-forward dynamics, so the
possibility of finding a low-'level', relatively-'discrete' TD E/I(up)
interjecting site, at which dysfunction can be 'fixed', is real.

k. p. collins

> 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
> response
> > (Llinas touted this for a while before the FALS/SOD link was
> found...antibodies
> > against the P-type channel). People have speculated on a glutamate
> excitotoxic
> > 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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