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Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University.

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Presentation on theme: "Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University."— Presentation transcript:

1 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 /1/A

2 SENESCENCE-RELATED INTRACELLULAR PATHOLOGIES Krisztián Kvell Molecular and Clinical Basics of Gerontology – Lecture 25 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 /1/A

3 TÁMOP /1/A Transcription Post-transcription DNA RNA mRNA Translation mRNA Nucleus Polypeptide Post-translation Covalent modification Chaperonins Cofactors Folding DegradationFunction AggregationRegulation Post-translational life of proteins

4 TÁMOP /1/A Protein turnover Decrease of proteasome activity Protein turnover Decrease of proteasome activity Oxidativel y modified proteins Protein synthesis Stress Proteins Hydroxy- nonenal protein adducts Glycation Exogenous Endogenous Protein modifications due to stress

5 TÁMOP /1/A 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 Lipufuscin, lysosomal waste

6 TÁMOP /1/A BACE  -secretase NICD Notch APP AβAβAβAβ APP cytoplasmic fragment Aβ plaque Oxidative stress Cell dysfunction and death Genes for neuronal plasticity and brain development Genes for neuronal plasticity and brain development Endoplasmicreticulum Nucleus Inside neuron Ca 2+ Neuronal EC A  plaques and their effects

7 TÁMOP /1/A Native state dimerization ProtofibrilBundlingFibrilBundling Misfold or molten globule amyloidogenic? Denatured state monomers monomers Colloidalconversion/folding UnstucturedAggregate Small amyloidogenic oligomers Amyloid Seeds Native state monomers monomers Native state dimers Amyloid seeds Filament MatureFibril Protofibril Protofibril elongation Fibril Filament Partialdenaturation Completedenaturation AmyloidogenicAggregation Polymerization Non-specific aggregation LAG PHASE GROWTH PHASE Amyloid fibril development and growth

8 TÁMOP /1/A Spontaneous changes Depurination and depyrimidination Deamination Single-strand breaks Spontaneous methylation Glycation Cross-linking Non-oxidative DNA damage

9 TÁMOP /1/A Biosynthetic errors Transcriptional errors Translational errors Racemization and isomerization Deamidation (asparagine and glutamine) Reactive carbonyl groups (non- oxidative) Serine dephosphorylation Non-oxidative protein damage

10 TÁMOP /1/A Protein turnover (high turnover = anti-aging strategy due to dilution) Increased levels of stress proteins, chaperons, ubiquitin (hormesis, training) Intramitochondrial proteolysis (Lon protease for miscoded and oxidized proteins, EGF↑) Modulation of non-oxidative protein damage

11 TÁMOP /1/A CR→fasting → hypoglycemia → decreased EC and IC glycation Lower insulin levels, higher proteasome functionality Higher NADPH ratio, better maintenance of glutathione in reduced form CR and non-oxidative protein damage

12 TÁMOP /1/A Transcriptional alterations, activity ↓ by 15-30% tRNA and aminoacylation mRNA processing and stability, ↓ total poly(A+) Translational alterations, ↓ protein synthesis, but calorie restriction can reinforce protein synthesis Efficiency and accuracy of protein synthesis ↓ Initiation, elongation, termination during protein synthesis, EF1a- activity ↓ by 35-45% Transcriptional and translational dysregulation in aging

13 TÁMOP /1/A Amyloid fibrils by AFM

14 TÁMOP /1/A Amyloid deposits by histology

15 TÁMOP /1/A Main non-lysosomal proteolytic machinery Activities include: -Chymotrypsin-like (CT-like) -Trypsin-like (T-like) -Peptidyl-glutamyl peptide hydrolase (PGPH) Not only housekeeping, but also involved in: -Apoptosis -Cell cycle -Cell differentiation Proteasome function

16 TÁMOP /1/A Degradation of oxidized, ubiquitinated proteins Proteasome function is compromised in aging Increased modification of macromolecules Increased load, lowered efficiency leading to immune- and neuronal senescence Proteasome function in aging

17 TÁMOP /1/A Lower insulin levels, higher proteasome functionality CR restores PGPH activity (↓ by 50% in aging ) Maintains / stimulates proteasome subunit (Rpt5) and activator (PA 28 a subunit) expression Healthy centenarians have normal proteasome activity Proteasome function in CR

18 TÁMOP /1/A Decreased IkB degradation, decreased NF-kB activation, immune decline CT-like activity decreases in T-cells Specific modification of 26S subunit, central in antigen processing Proteasome function in immune senescence

19 TÁMOP /1/A CT-like activity drops (not in cerebellum / brain stem) Proteasome decline enhances neuronal vulnerability Accumulation, aggregation of damaged proteins Increase in Lewis bodies, huntingtin fragments Role in pathogenesis of Alzhemier’s, Parkinson’s Amplification of lipofuscin, threshold phenomenon Proteasome function in neuronal senescence

20 TÁMOP /1/A Fusion Sequestration LC3-II LC3-I Raptor PRAS40 Atg1 VPS15 PI3K III mTOR Autophag y inductio n Amino Acids Apoptosi s Phagophore Lysosome AutophagosomeAutophagolysosome MembraneNucleation Bcl-xL Apaf -1 Autophagy and IC breakdown Genotoxic stress / p53 Genotoxic stress / p53 AMPK signalli ng AMPK signalli ng MAPK / Erk1/2 signalling MAPK / Erk1/2 signalling PI3K / Akt signallin g PI3K / Akt signallin g Beclin1 GβL

21 TÁMOP /1/A conversio n normal prion abnormal prion Prion protein conversion

22 TÁMOP /1/A NORMAL CJD KURU SCRAPIE Histology in prion protein- related diseases

23 TÁMOP /1/A LaminA mutation (nuclear envelope fragility) Primerily affects mesenchymal tissues HGPS cells have decreased stress resistence Progeria causing premature death Hutchinson-Guilford progeria syndrome

24 TÁMOP /1/A N BAF Nurim LBR C N C LAP-1 N C Emerin MAN-1 N C LAP2β N C N C Chromatin Chromatin Lamin A/C Lamin B LAP2α Nuclear pore complex Endoplasmaticreticulum Inner memrane Outer memrane Cytoplasm Nucleoplasm HP1 N C LEM domain Composition of nuclear envelope

25 TÁMOP /1/A NUCLEAR FRAGILITY CHROMATIN REORGANIZATION MISLOCALIZATION OF IM PROTEINS IN ER ER-RETENTION NUCLEAR ANCHORAGE Outer Membrane LAP Nuclear Pore Complex Endoplasmic Reticulum Inner Membrane Emerin Heterochromatin Actin SUN/ANC Lamins Nuclear envelope-related instability


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