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Hey de Grey, real scientists are starting to realize the TRUTH: Neuronal inclusions are good for you!

[posted on behalf of CRON4healthyfuture 2006-03-07]

Lift up a pint of Guiness to this one de Grey, and see the light! Mass Gen Yankee wizardry beats the meandering imagination of an ersatz intellectual.

[ All right, I know, you can nit-pick anything, and they did not find benefit in Alzheimer's or lipofuscin accumulation, which are presumably "more" age-related. But the general principle is illustrative, in my opinion, never humble. ]

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http://www.pnas.org/cgi/content/abstract/0511256103v1

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"One approach to the development of therapeutic intervention for these diseases has been to identify chemical compounds that reduce the size or number of inclusions. We have, however, identified a compound that promotes inclusion formation in cellular models of both Huntington's disease and Parkinson's disease. Of particular interest, this compound prevents huntingtin-mediated proteasome dysfunction and reduces -synuclein-mediated toxicity. These results demonstrate that compounds that increase inclusion formation may actually lessen cellular pathology in both Huntington's and Parkinson's diseases, suggesting a therapeutic approach for neurodegenerative diseases caused by protein misfolding."

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[MR]

CRON4healthyfuture wrote:

> [ All right, I know, you can nit-pick anything, and they [1] did not find benefit in Alzheimer's or lipofuscin accumulation, which are presumably "more" age-related. But the general principle is illustrative, in myopinion, never humble. ]

Sure. There is a still-little-publicized but quite respectable body of
research to suggest that the most direct mediators of neuronal
dysfunction in many neurodegnerative diseases is not the fully-formed,
visible inclusions and aggregates (stuff like Tau tangles or amyloid
plaque in Alzheimer's, and even more strongly Huntingtin inclusions in
HD (tho' this is not a disease of aging, as you note), but the monomeric
or oligomeric precursors -- short, soluble chains of beta-amyloid, eg.
To that extent, the aggregates may even be BENEFICIAL *in the short
term* , by forming nucleating "sinks" that sequester & thus render
inert these bioactive nasties. Indeed, on HD specifically, this report echoes (4) from a couple of years back, which found that "Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death". (4) was merely correlative evidence, however, while (1) is much more impressive experimental stuff.

This is why Aubrey de Grey (the guy that your subject line is presumably
intended to taunt) remains pessimistic (but not dogmatically so) about
the likely efficacy, esp long-term, of "beta-breakers" (2): you may just
wind up liberating the oligomers, setting them free to do their dirty work.

As he says (3),

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Intense debate rages concerning whether these structures 1) cause the
cognitive decline of Alzheimer’spatients, 2) are harmless epiphenomena
or 3) are positively beneficial in retarding the disease [ref]. However,
if they are beneficial, it must be the aggregation of their main
component protein (amyloid beta, Abeta) that is beneficial and not the
actual aggregates, as the latter are necessarily inert by virtue of
their low surface-to-volume ratio. Thus, it is reasonable to pursue
ways in which senile plaques could be removed. A strategy for
eliminating such aggregates is to dissolve them. However, this would
increase the concentration of the monomeric or oligomeric proteins of
which the aggregate was composed. If aggregation is indeed a defence
against excessive concentrations of a toxic protein that (for whatever
reason) cannot be cleared, reversing aggregation will be deleterious.
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The new report to which you (CRON4healthyfuture) have drawn our attention (1) is consistent with that view:"a compound that promotes inclusion formation in cellular models ... prevents huntingtin-mediated proteasome dysfunction and reduces -synuclein-mediated toxicity."(1) The huntingtin aggregates are relatively inert, & not available for proteasomal attack, and thus can't get stuck (literally) in the proteasomal machinery & thus disable their ability to perform essential cellular garbage disposal and recycling.

OTOH, it's pretty clear that just leaving aggregates to accumulate -- or
promoting their formation -- will eventually become problematic, as it
slows down intracellular trafficking, dilutes enzymes, interferes with neuronal electrical activity, generates surface-to-volume problems with a variety of cellular components, and creates a vicious cycle of self-reinforcing inefficiency in the cell's ability to degrade defective organelles & recycle their components by hampering lysosomal degradative capacites. To this extent, the new study (1) and the previous one (4) are somewhat misleading, as both studes used a cell culture model with no neurites involved (unlike the brain), so the transport problems generated by aggregates would not be so much of a problem, making the later issues that would emerge in vivo invisible to the experiment.

And also, it's pretty much unambiguous that reducing the amount of inclusions formed by the less problematic method of reducing the formation of the precursors, or getting RID of them BEFORE they have the chance to aggregate (rather than reducing the choice to either aggregating or remaining as soluble precursors within conditions of equal absolute quantity of the nasty in question), prevents the disease and/or its cellular phenome. This is quite clear in AD for beta-amyloid, and even in the case of HD, where the evidence for the "benefits" of aggregation seem strongest, many studies have shown that eaerly increases in autophagy or proteasome activity, by reducing the initial formation thereof, can reduce toxicity; see a lot of Rubinsztein's work on some of your (CRON4healthyfuture's) favorite topics: TOR and rapamycin in autophagy (5,6). The problem, of course, is that the lever-jerking of metabolism always comes with negative side-effects, as the case of gamma-secretase inhibitors for AD seems to have again shown.

That's exactly the advantage of the SENS intervention for these (immune-mediated phagocytosis (3) and lysosomal xenohydrolase enhancement (8,9)): completely remove and eliminate the aggregates down to their constituents, instead of just dissolving them, thus avoiding the potential risk of liberating the evil precursor molecules while avoiding fighting with the tarbaby of interfering with the metabolic processes leading up to their formation. No matter which theory of pathogenesis is correct, the gak is gone and the patient wins.

-MR

1: Bodner RA, Outeiro TF, Altmann S, Maxwell MM, Cho SH, Hyman BT,
McLean PJ,
Young AB, Housman DE, Kazantsev AG.
From the Cover: Pharmacological promotion of inclusion formation: A
therapeutic
approach for Huntington's and Parkinson's diseases.
Proc Natl Acad Sci U S A. 2006 Mar 14;103(11):4246-51. Epub 2006 Mar 6.
PMID: 16537516 [PubMed - in process]
http://www.pnas.org/cgi/content/short/103/11/4246

2. McGeer EG, McGeer PL.
Abeta immunotherapy and other means to remove amyloid.
Curr Drug Targets CNS Neurol Disord. 2005 Oct;4(5):569-73. Review.
PMID: 16266289 [PubMed - indexed for MEDLINE]

3. de Grey AD.
Foreseeable pharmaceutical repair of age-related extracellular damage.
Curr Drug Targets. 2005, in press.
http://www.gen.cam.ac.uk/sens/excellPP.pdf

4. Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S.
Inclusion body formation reduces levels of mutant huntingtin and the risk of
neuronal death.
Nature. 2004 Oct 14;431(7010):805-10.
PMID: 15483602 [PubMed - indexed for MEDLINE]

5. Ravikumar B, Berger Z, Vacher C, O'kane CJ, Rubinsztein DC.
Rapamycin pre-treatment protects against apoptosis.
Hum Mol Genet. 2006 Apr 1;15(7):1209-16. Epub 2006 Feb 23.
PMID: 16497721 [PubMed - in process]

6. Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F,
Easton DF, Duden R, O'Kane CJ, Rubinsztein DC.
Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine
expansions in fly and mouse models of Huntington disease.
Nat Genet. 2004 Jun;36(6):585-95. Epub 2004 May 16.
PMID: 15146184 [PubMed - indexed for MEDLINE]

7. Rubinsztein DC.
Macroautophagy upregulation - a candidate therapeutic strategy to enhance clearance of toxic intracellular aggregate-prone proteins
Rejuvenation Res. 2005 Sep;8(Suppl 1):S47(Abs 96).
http://www.sens.org/sens2/abs/Rubinsztein.htm

8. de Grey AD. Appropriating microbial catabolism: A proposal to treat and prevent neurodegeneration. Neurobiol Aging. 2005 Oct 1; [Epub ahead of print] PMID: 16207503 [PubMed - as supplied by publisher]
http://www.gen.cam.ac.uk/sens/NBA-PP.pdf

9: de Grey AD, Alvarez PJ, Brady RO, Cuervo AM, Jerome WG, McCarty PL,
Nixon RA, Rittmann BE, Sparrow JR.
Medical bioremediation: Prospects for the application of microbial
catabolic diversity to aging and several major age-related diseases.
Ageing Res Rev. 2005 Aug;4(3):315-38.
PMID: 16040282 [PubMed - in process]
http://www.gen.cam.ac.uk/sens/medbioremPP.pdf