From: Rafal Smigrodzki (rafal@smigrodzki.org)
Date: Tue Apr 22 2003 - 14:54:59 MDT
Aubrey wrote:
>
> Rafal Smigrodzki wrote:
>
>> ### Do you think that protein aggregation is causative in sporadic AD
>> or PD, or that it is involved in the pathomechanism at some later
>> stage, perhaps amplifying the damage caused by other factors?
>> Recently it turned out that APP has a direct toxic effect on
>> mitochondria, and mutant alpha-synuclein has also been implicated in
>> diminished mito function.
>
> It's still very unclear what the major pathogenic process is in AD or
> PD, but the various aggregates seem to be the only options, because
> nothing else has been identified that changes in affected cells
> (either with age or faster in the disease than in normal aging).
### What about mtDNA mutations? They are accumulating to a very significant
degree, see recent work by Simon and Flint Beal
-----------------
The
> effect on mitochondria is interesting, but basically I think that we
> can be sure that these aggregates are bad for us, so let's get rid of
> them, rather than wasting time worrying about precisely how they're
> bad for us.
### If there is a different underlying process, dealing with the aggregates
will not remove all of the problem, although it could ameliorate some of it.
I would rather try to attack the ultimate cause, which most likely doesn't
involve the proteins that actually aggregate (except in Huntington's, DRPLA,
and other classic triplet expansion diseases).
-----------------------------
>
>> Also, are protein aggregates in AD and PD really lysosomal, or
>> cytoplasmic (or even extracellular)?
>
> In AD, the Abeta aggregates (plaques) are extracellular but can be
> made lysosomal by vaccination (Elan's work, etc). Vaccination makes
> microglia engulf (endocytose) bits of plaque. It thereby becomes
> lysosomal.
### Yes, but in the absence of Elan, amyloid is extralysosomal, so it
couldn't act by choking the lysosomes, and putting xenoenzymes in this
compartment will not allow amyloid removal.
-------------------------
As for tau (tangles) in AD and alpha-synuclein in PD, the
> evidence that it is lysosomal is limited but positive: see eg
> Neurosci Lett 284:187 or Mol Cell Neurosci 18:702. It would be very
> surprising if it weren't, because the stuff is clearly accumulating
> to the detriment of the cell. In some neurodegenerative diseases
> there seem to be nuclear aggregates, but that is very much the
> exception.
### Is there some alpha-synuclein in lysosomes simply because stuff ends up
in lysosomes, or is it's presence in the lysosomes the mechanism of its
detrimental action? This has not been answered so far, AFAIK.
----------------------
>
>> Atheromas are not aggregates of lysosomally indigestible material, so
>> improving cellular digestion is not likely to be of help.
>
> Wrong. First, plaques develop from foam cells, which are macrophages
> that have endocytosed modified LDL in the artery wall and failed to
> digest it all, which is why they became foam cells. Second, in a
> mature plaque there is a constant influx of new macrophages that
> enter it for the purpose of breaking down the core, and they engulf
> bits of it, but they can't break it down so they die and become part
> of the problem.
### Atheromatous material may be difficult to digest, but is not
non-digestible. With some treatments you can have regression of
atherosclerotic changes implying digestion of macroscopic amounts of plaque.
There is a dynamic balance between plaque accumulation and digestion.
Macrophages can eat incredibly tough stuff, even bacterial cell membranes.
Rafal
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