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Senescence-related intracellular pathologies

Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011.

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Senescence-related intracellular pathologies

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  1. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

  2. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Krisztián Kvell Molecular and Clinical Basics of Gerontology – Lecture 25 Senescence-relatedintracellularpathologies

  3. Post-translational life of proteins Translation mRNA mRNA Post- transcription Post-translation Covalentmodification Chaperonins Cofactors RNA Polypeptide Nucleus Transcription DNA Folding Degradation Function Aggregation Regulation

  4. Protein modificationsduetostress Endogenous Exogenous Stress Proteins Protein turnover Decrease of proteasomeactivity Glycation Hydroxy-nonenalprotein adducts Protein synthesis Oxidativelymodifiedproteins

  5. Lipufuscin, lysosomal waste • Lysosomes fail to digest all aged macromolecules • Waste: brown-yellow, autofluorescent, electron-dens, granules called lipofuscin, ceroid, age-pigment • Increased oxidization, especially in presence of iron • Mitochondria are major generators of lipofuscin • May occupy up to 75% of perikaryon in neurons • Forms amyloid, role in Alzheimer’s, Parkinson’s

  6. Neuronal EC A plaques and their effects Notch Aβ plaque Nicastrin Nicastrin APP APH-1 APH-1 BACE Presenilin-1 Presenilin-1 Oxidative stress PEN-2 PEN-2 Aβ Inside neuron Cell dysfunction and death -secretase NICD APP cytoplasmic fragment Ca2+ Endoplasmic reticulum Genes for neuronal plasticity and brain development Ca2+ Nucleus

  7. Amyloid fibril development and growth LAG PHASE GROWTH PHASE Native state dimerization Native state monomers Native state dimers Partial denaturation Small amyloidogenic oligomers Protofibril Bundling Fibril Bundling Amyloidogenic Aggregation Polymerization Misfold or moltenglobule amyloidogenic? Mature Fibril Complete denaturation Filament Protofibril Amyloid Seeds Colloidal conversion/ folding Filament elongation Protofibril elongation Fibril elongation Non-specific aggregation Denatured state monomers Unstuctured Aggregate Amyloidseeds

  8. Non-oxidative DNA damage • Spontaneouschanges • Depurination and depyrimidination • Deamination • Single-strandbreaks • Spontaneousmethylation • Glycation • Cross-linking

  9. Non-oxidative protein damage • Biosyntheticerrors • Transcriptionalerrors • Translationalerrors • Racemization and isomerization • Deamidation (asparagine and glutamine) • Reactivecarbonylgroups (non-oxidative) • Serinedephosphorylation

  10. Modulation of non-oxidativeprotein damage • Protein turnover (highturnover = anti-agingstrategyduetodilution) • Increasedlevels of stressproteins, chaperons, ubiquitin (hormesis, training) • Intramitochondrialproteolysis (Lonproteaseformiscoded and oxidizedproteins, EGF↑)

  11. CR and non-oxidative protein damage • CR→fasting → hypoglycemia → decreased EC and IC glycation • Lowerinsulinlevels, higherproteasomefunctionality • Higher NADPH ratio, bettermaintenance of glutathioneinreducedform

  12. Transcriptional and translational dysregulation in aging • Transcriptionalalterations, activity ↓ by 15-30% • tRNA and aminoacylation • mRNAprocessing and stability, ↓ totalpoly(A+) • Translationalalterations, ↓ protein synthesis, butcalorierestrictioncanreinforceproteinsynthesis • Efficiency and accuracy of protein synthesis ↓ • Initiation, elongation, terminationduring protein synthesis, EF1a-activity ↓ by 35-45%

  13. Amyloidfibrilsby AFM

  14. Amyloid deposits by histology Amyloiddeposits Esophagus

  15. Proteasome function • Main non-lysosomalproteolyticmachinery • Activitiesinclude: • Chymotrypsin-like (CT-like) • Trypsin-like (T-like) • Peptidyl-glutamyl peptide hydrolase (PGPH) • Notonlyhousekeeping, butalsoinvolvedin: • Apoptosis • Cellcycle • Celldifferentiation

  16. Proteasome function in aging • Degradation of oxidized, ubiquitinated proteins • Proteasomefunction is compromisedinaging • Increasedmodification of macromolecules • Increasedload, loweredefficiencyleadingtoimmune- and neuronalsenescence

  17. Proteasome function in CR • Lowerinsulinlevels, higherproteasomefunctionality • CR restores PGPH activity (↓ by 50% inaging ) • Maintains / stimulatesproteasomesubunit (Rpt5) and activator (PA 28 a subunit) expression • Healthycentenarianshavenormalproteasomeactivity

  18. Proteasome function in immune senescence • DecreasedIkBdegradation, decreasedNF-kBactivation, immunedecline • CT-likeactivitydecreasesinT-cells • Specificmodification of 26S subunit, centralinantigenprocessing

  19. Proteasome function in neuronal senescence • CT-likeactivitydrops (notincerebellum / brainstem) • Proteasomedeclineenhancesneuronalvulnerability • Accumulation, aggregation of damagedproteins • Increasein Lewis bodies, huntingtinfragments • Roleinpathogenesis of Alzhemier’s, Parkinson’s • Amplification of lipofuscin, thresholdphenomenon

  20. Autophagy and IC breakdown PI3K / Akt signalling MAPK / Erk1/2 signalling AMPK signalling Genotoxic stress / p53 mTOR Amino Acids Raptor GβL PRAS40 VPS15 Autophagy induction Atg1 PI3K III Apoptosis Beclin1 Bcl-xL Membrane Nucleation Apaf-1 Sequestration Atg5 Phagophore Atg7 Fusion Atg12 Atg3 Atg10 Autophagosome Autophagolysosome Atg16 LC3-II Atg4 Atg7 Lysosome LC3-I

  21. Prion protein conversion conversion normal prion abnormal prion

  22. Histology in prion protein-related diseases NORMAL KURU CJD SCRAPIE

  23. Hutchinson-Guilfordprogeriasyndrome • LaminAmutation (nuclearenvelopefragility) • Primerilyaffectsmesenchymaltissues • HGPS cellshavedecreasedstressresistence • Progeriacausingprematuredeath

  24. Composition of nuclearenvelope Endoplasmatic reticulum C Nuclearpore complex Innermemrane Cytoplasm C Nurim LAP-1 Emerin MAN-1 C LAP2β LBR C N Outermemrane Lamin B N BAF N BAF Lamin A/C C Nucleoplasm BAF C HP1 N N C N LAP2α Chromatin BAF Chromatin N LEM domain

  25. Nuclearenvelope-relatedinstability MISLOCALIZATION OF IM PROTEINS IN ER ER-RETENTION EndoplasmicReticulum Emerin NuclearPoreComplex LAP OuterMembrane Lamins Actin InnerMembrane Heterochromatin NUCLEAR FRAGILITY CHROMATIN REORGANIZATION SUN/ANC NUCLEAR ANCHORAGE

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