NUCLEOLAR DISRUPTION IN AUTOIMMUNE AND NEURODEGENERATIVE DISEASES
Notice bibliographique
Résumé
PV099 / #84 Poster Topic: AS12 - Genetics, Epigenetics, Transcriptomics Background/Purpose Autoimmune disease tautology (ie, common features of autoimmune diseases such as female predominance among patients) suggests there may be similar cellular level mechanisms in many autoimmune diseases with the subsequent symptoms varying based on the cell type, triggers involved, and immune system accessibility. This tautology can also include Alzheimer’s and other neurodegenerative diseases. The purpose of this project was to search published research to develop a mechanistic hypothesis based on synergies among these diseases. Methods The author’s previously published hypothesis, the “X chromosome-nucleolus nexus” which focused primarily on lupus, provided a starting point. That hypothesis proposed that nucleolar dynamics during extraordinary cellular stress could disrupt the inactive X chromosome (Xi; aka, the “nucleolar satellite” or Barr body). This could open expression of normally silent X-linked polyamine enzyme alleles and an abundance of Alu elements on the Xi. Increased polyamine metabolism could drive further nucleolar dynamics. RNA polymerase III generated Alu RNA transcripts could competitively bind nucleolin, disrupting the nucleolar shell normally stabilized by nucleolin and structural RNAs. Disruption of the nucleolar shell could release autoantigenic material leading to the lupus autoimmune reaction. Online queries (eg, PubMed) with key word combinations (eg, nucleolin, lupus, Alzheimer’s) were used and retrieved research results that supported potential abnormalities in polyamine metabolism, disruption of peri-nucleolar chromatin, abnormal expression of Alu elements, and loss of nucleolar integrity. Results It was found that many aspects of Alzheimer’s and other diseases could be explained by expansion of the original “X chromosome-nucleolus nexus” hypothesis and such expansion gives further details for the original lupus hypothesis. When key genes in Alzheimer’s were queried, it was found that they were in peri-nucleolar chromatin: presenilin-1 on chromosome 14; amyloid precursor protein on chromosome 21; tau on chromosome 17, and ApoE4 on chromosome 19. Chromosomes 14 and 21 with nucleolar organizing regions are in the nucleolar shell and chromosomes 17 and 19, with DNA repair genes, are associated with the nucleolus (ie, TADs, topological associated domains) to assist in the nucleolar function of DNA repair. Therefore, nucleolar dynamics could potentially adversely impact epigenetic control in these peri-nucleolar chromosomes. Alu elements comprise 11% of the human genome, with more than 1 million Alu copies, whereas non-primate animals do not have Alu elements. Alu elements account for 28.8% of the pseudo-autosomal region 1 (PAR1) of the X chromosome (~2,500 Alu copies). The chromosome 22 long arm (22q) in the nucleolar shell is 18% Alu, chromosome 19 is 25.8% Alu, chromosome 17 is 18% Alu with 30% in 17p13.3. Such Alu clusters could have a significant role in disruption of the nucleolus in lupus, Alzheimer’s and other autoimmune and neurodegenerative diseases. Conclusions The hypothesis proposes mutual disruption of the nucleolus and peri-nucleolar chromatin in these diseases with loss of epigenetic control that allows altered expression of Alzheimer’s related genes and, in lupus, formation of autoantigens, many of which are components of the nucleolus. Increased polyamine metabolism (eg, triggered by EBV or UV light) can reduce S-adenosylmethionine (SAM) which, at low levels seen in Alzheimer’s, can induce tau phosphorylation by p38 kinase followed by polyamine-induced aggregation of hyperphosphorylated tau. Polyamine recycling can reduce acetyl-CoA leading to low acetylcholine seen in Alzheimer’s. This hypothesis suggests new directions for therapeutic research in autoimmune and neurodegenerative diseases.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,002 | 0,002 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,000 | 0,001 |
| Intégrité de la recherche | 0,001 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,017 | 0,004 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».