Perhaps we could have a 'Guess the Real Ron' fund raising competition.................organised by ALS/TDI ?

http://talesofcuriosity.com/v/HenrysWives/i/HenryVIII-3.jpg ( ? )

Ron gives a speech...

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-- Le Meilleur Vin Avec Les Meilleurs Amis --

The comment above is my personal opinion. I do not represent ALS-TDI

You guys are as funny as a case of clap. Lol. It's nice to be loved..

My mutant peckers are clap resistant................

http://www.bbc.co.uk/news/uk-scotland-edinburgh-east-fife-12745163

DNA Repair (Amst). 2011 Feb 7;10(2):199-209. Epub 2010 Nov 26.
Role of senataxin in DNA damage and telomeric stability.
De Amicis A, Piane M, Ferrari F, Fanciulli M, Delia D, Chessa L.
SourceII School of Medicine, Department of Clinical and Molecular Medicine, University La Sapienza, Roma, Italy. andrea.deamicis@unirom

Abstract
Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive neurodegenerative disorder characterized by cerebellar ataxia and oculomotor apraxia. The gene mutated in AOA2, SETX, encodes senataxin (SETX), a putative DNA/RNA helicase. The presence of the helicase domain led us to investigate whether SETX might play a role in DNA damage repair and telomere stability. We analyzed the response of AOA2 lymphocytes and lymphoblasts after treatment with camptothecin (CPT), mitomycin C (MMC), H₂O₂ and X-rays by cytogenetic and Q-FISH (quantitative-FISH) assays. The rate of chromosomal aberrations was normal in AOA2 cells after treatment with CPT, MMC, H₂O₂ and X-rays. Conversely, Q-FISH analysis showed constitutively reduced telomere length in AOA2 lymphocytes, compared to age-matched controls. Furthermore, CPT- or X-ray-induced telomere shortening was more marked in AOA2 than in control cells. The partial co-localization of SETX with telomeric DNA, demonstrated by combined immunofluorescence-Q-FISH and chromatin immunoprecipitation, suggests a possible involvement of SETX in telomere stability.

Copyright © 2010 Elsevier B.V. All rights reserved.

PMID:21112256[PubMed - in process]

I have proposed that the binding of CHIP to mutant SOD1 results in reduced telomerase activity. The authors above state that "Overexpression of CHIP prevents nuclear translocation of hTERT and promotes hTERT degradation in the cytoplasm, thereby inhibiting telomerase activity". Telomerase is necessary to maintain telomere length. Short telomeres are associated with ageing.

The first study here finds that ISG15 is upregulated with telomere shortening. Increased ISG15 is reported in ALS and is a proposed biomarker for neuroinflammation in general.

Mary


Aging (Albany NY). 2009 Jul 17;1(7):608-21.
Telomere length regulates ISG15 expression in human cells.
Lou Z, Wei J, Riethman H, Baur JA, Voglauer R, Shay JW, Wright WE.
Source
Department of Cell Biology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.

Abstract
Endogenous genes regulated by telomere length have not previously been identified in human cells. Here we show that telomere length regulates the expression of interferon stimulated gene 15 (ISG15, 1p36.33). ISG15 expression (RNA and protein) increases in human cells with short telomeres, and decreases following the elongation of telomeres by human telomerase reverse transcriptase (hTERT). The short-telomere-dependent up-regulation of ISG15 is not mediated by replicative senescence/DNA damage signaling or type I interferons. In human skin specimens obtained from various aged individuals, ISG15 is up-regulated in a subset of cells in older individuals. Our results demonstrate that endogenous human genes can be regulated by the length of telomeres prior to the onset of DNA damage signals, and suggest the possibility that cell turnover/telomere shortening may provide a mechanism for adjusting cellular physiology. The upregulation of ISG15 with telomere shortening may contribute to chronic inflammatory states associated with human aging.

PMID:
20157543
[PubMed - indexed for MEDLINE]
PMCID:
PMC2806043

http://flintbox.com/public/project/18472/
Technology

Researchers from Sanford Burnham identified nine interferon-stimulated genes (ISGs) that were up-regulated in the spinal cord of SOD1(G93A) ALS mouse model. Most notably they could be detected at a presymptomatic age, about 30 days before onset of disease. The up-regulation was observed specifically in astrocytes surrounding motor neurons of these genes suggesting neuroinflammation related to innate immunity is triggered by the disease. Among identified ISGs, ISG15 seems particularly amenable to be developed as a general neuroinflammation biomarker. Its overexpression was additionally observed in traumatic brain injury, stroke and HIV-induced dementia models. ISG15 is an ubiquitin-like molecule and conjugate to target protein upon activation. Researchers at Sanford Burnham have developed an antibody targeting ISG15 and currently they are conducting a screen for small molecules. The idea is to further develop these molecules and antibodies by tagging them with radioactive/imaging agents that would enable detection of ISG15 and establish the onset of pathological process.

Duke and I had proposed some time back that Gleevec warranted attention as a possible therapeutic for ALS.

I'd posted a copy of a comment sent to the Alzheimer Research Forum, which I'll post again here as it would seem to validate this proposal . Gleevec inhibits c-Abl and inhibition of c-Abl increases telomerase activity. We had looked at quite a complex mechanism and came to the conclusion that the c-Abl pathway is upregulated in ALS.

This comment relates to AD, but we now see that TDP-43 affects APP processing.

http://www.als-tdf.org/forum/yaf_postst45808p2_ATN224----Choline-tetrathiomolybdate.aspx

Comment by: Mary Reid
Submitted 3 December 2004 Posted 6 December 2004



It's very interesting that Fu and colleagues report that their findings "demonstrate a requirement for telomerase in the cell survival-promoting actions of BDNF and sAPP in early postmitotic hippocampal neurons."
Kharbanda et al. (1) report that c-Abl phosphorylates human telomerase reverse transcriptase (hTERT), a telomerase component, and inhibits hTERT activity, while the Beitzinger group (2) find "expression of p73 in telomerase-positive H1299 cells results in rapid downregulation of hTERT promoter activity, hTERT mRNA expression and loss of telomerase activity."

The recent study by Alvarez et al. (3) that Aβ peptide fibrils and reactive oxygen species induce an increase of c-Abl activity in rat hippocampal neurons as well as an increase in nuclear p73 protein levels, and that the neuronal cell death induced by Aβ was prevented by Gleevec, would seem to add further to the puzzle.

The Wilson group report that in AD hippocampus, increased levels of p73 are located in the nucleus of pyramidal neurons and p73 is located in dystrophic neurites and cytoskeletal pathology.

Is Aβ a down-regulator of telomerase activity?

Bakalova et al. have reported that inhibition of c-Abl results in increased telomerase. Gleevec, a c-Abl inhibitor (and an inhibitor of amyloid-β production; see Netzer et al., 2003) would then be expected to increase telomere length. Of further interest is the finding by Epel and colleagues that life stress is associated with telomere shortening. They suggest that the stress hormone response may cause oxidative stress. Might we then expect increased expression of c-Abl in this group?

Mary,
It is not known whether reduction of beta-amyloid is a feasible way of treating Alzheimer's, as an anti-beta-amyloid vaccine has been shown to clear the brain of plaques without having any effect on Alzheimer symptoms.

I did come across a paper some time ago that suggested that the production of beta-amyloid was a protective mechanism used against invading pathogens but can't find it right now.
I'll post again when I find it.

---

Into the heart, an air that kills, from yon far country blows.
What are those blue remembered hills, what sphires what farms are those.
That is the land of lost content,I see it shining plain,
The happy highways where I went and cannot come again

What happens to this process as Abeta depletes dynamin?



"TLR4 subsequently undergoes dynamin-dependent endocytosis and is trafficked to the endosome, where it forms a signaling complex with TRAM and TRIF"



https://rowan.biology.ualberta.ca/courses/imin401/uploads/winter10/public/papers/4TLRreviewAkira.pdf

TLR4 is the only TLR that uses all four adaptors and activates both the MyD88- and TRIF-dependent pathways (Fig. 1). TLR4 initially recruits TIRAP at the plasma membrane and subsequently facilitates the recruitment of MyD88 to trigger the initial activation of NF-κB and MAPK45. TLR4 subsequently undergoes dynamin-dependent endocytosis and is trafficked to the endosome, where it forms a signaling complex with TRAM and TRIF, rather than TIRAP and MyD88, to initiate the TRIFdependent pathway that leads to IRF3 activation as well as the late-phase activation of NF-κB and MAPK46–48. Thus, TLR4 activates the MyD88-dependent pathway earlier than the TRIF-dependent pathway. Notably, activation of both the MyD88- and TRIF-dependent pathways is necessary for the induction of inflammatory cytokines via TLR4 signaling, which is in contrast to other TLRs, for which activation of either the MyD88- or the TRIF-dependent pathway is sufficient for the induction of inflammatory cytokines. It is still a mystery why activation of either pathway alone is insufficient for the induction of inflammatory cytokines via TLR4 signaling

http://www.alzforum.org/new/detail.asp?id=2538

A Toll on Memory: New Role for Immune-Related Receptor in Brain

"In microglia, TLR2 and TLR4 bind fibrillar Aβ and are essential for microglial activation, which leads to inflammation and production of reactive oxygen species (see Jana et al., 2008 and ARF related news story on Reed-Geaghan et al., 2009). TLR4 in neurons also contributes to neuronal apoptosis due to Aβ (see Tang et al., 2008)."

Curr Alzheimer Res. 2012 Jan 23. [Epub ahead of print]
Common variants in toll-like receptor 4 confer susceptibility to Alzheimer's disease in a Han Chinese population.
Yu JT, Miao D, Cui WZ, Ou JR, Tian Y, Wu ZC, Zhang W, Tan L.
Source
Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No.5 Donghai Middle Road, Qingdao 266071, PR China. dr.tanlan@163.com.

Abstract
Toll-like receptor 4 (TLR4) represents a reasonable functional and positional candidate gene for Alzheimer's disease (AD) as it is located within the previous identified linkage region of AD on chromosome 9q, and functionally is involved in the microglia-mediated inflammatory response, amyloid-β (Aβ) plaque formation and Aβ clearance. To test whether variants in the TLR4 gene are associated with late-onset AD (LOAD), we organized a multicenter study of 785 subjects (399 cases and 386 matched controls) in a Han Chinese population. Ten single nucleotide polymorphisms (SNPs) that span the TLR4 gene, from approximately 5 kb of the predicted 5'-untranslated region (UTR) to approximately 6 kb of the predicted 3'- UTR, were selected and their associations with LOAD risk factors were assessed. With respect to allelic diversity, the minor alleles of seven SNPs (rs10759930, rs1927914, rs1927911, rs12377632, rs2149356, rs7037117, and rs7045953) in TLR4 showed consistent protective effects against the risk of developing LOAD. With regard to genotypic diversity, individuals carrying at least one minor allele of each SNP above had a consistently lower risk of LOAD than those with no copies of the minor alleles (ORs ranging from 0.445 to 0.637). rs7045953, located in the 3'-UTR of TLR4, was most strongly associated with LOAD, and when incorporated into a haplotype with rs10759930, the strongest association was detected (P = 1.7×10-6, Pc =1.0×10-4). Our data suggests that the TLR4 gene contributes to the susceptibility for LOAD in Han Chinese.

PMID:
22272615
[PubMed - as supplied by publisher]
Exp Neurol. 2011 Dec;232(2):143-8. Epub 2011 Aug 22.
High-mobility group box-1 impairs memory in mice through both toll-like receptor 4 and Receptor for Advanced Glycation End Products.
Mazarati A, Maroso M, Iori V, Vezzani A, Carli M.
Source
Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1752, USA. mazarati@ucla.edu

Abstract
High-mobility group box-1 (HMGB1) is a nuclear protein with cytokine-type functions upon its extracellular release. HMGB1 activates inflammatory pathways by stimulating multiple receptors, chiefly toll-like receptor 4 (TLR4) and Receptor for Advanced Glycation End Products (RAGE). TLR4 and RAGE activation has been implicated in memory impairments, although the endogenous ligand subserving these effects is unknown. We examined whether HMGB1 induced memory deficits using novel object recognition test, and which of the two receptor pathways was involved in these effects. Non-spatial long-term memory was examined in wild type, TLR4 knockout, and RAGE knockout mice. Recombinant HMGB1 (10μg, intracerebroventricularly, i.c.v.) disrupted memory encoding equipotently in wild type, TLR4 knockout and RAGE knockout animals, but affected neither memory consolidation, nor retrieval. Neither TLR4 knockout nor RAGE knockout mice per se, exhibited memory deficits. Blockade of TLR4 in RAGE knockout mice using Rhodobacter sphaeroides lipopolysaccharide (LPS-Rs; 20 μg, i.c.v.) prevented the detrimental effect of HMGB1 on memory. These data show that elevated brain levels of HMGB1 induce memory abnormalities which may be mediated by either TLR4, or RAGE. This mechanism may contribute to memory deficits under various neurological and psychiatric conditions associated with the increased HMGB1 levels, such as epilepsy, Alzheimer's disease and stroke.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID:
21884699
[PubMed - indexed for MEDLINE]
PMCID:
PMC3202022
[Available on 2012/12/1]