![HD: progressive, autosomal dominant
hereditary neurodegenerative disorder
induces the selective apoptosis of neurons
in striatum and cortex.
HttEx1-poly(Q) amino-terminal fragments
Repeats < 35-38 CAG residues :soluble,harmless,
But repeat > than 38 CAG residue: toxic,insoluble
aggregates/neuronal apoptosis
Mutation: unstable expansion of CAG
[glutamine(Q)] triplets 17 codons downstream
of the initiator ATG in exon1 (Ex1) of the 67
exons containing huntingtin gene.
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The role of Oxydative stress in toxicity inhibition mediated by polyQ huntingtin protein aggregates: Role of Heat shock Protein
- 2. HD: progressive, autosomal dominant hereditary neurodegenerative disorder induces the selective apoptosis of neurons in striatum and cortex. HttEx1-poly(Q) amino-terminal fragments Repeats < 35-38 CAG residues :soluble,harmless, But repeat > than 38 CAG residue: toxic,insoluble aggregates/neuronal apoptosis Mutation: unstable expansion of CAG [glutamine(Q)] triplets 17 codons downstream of the initiator ATG in exon1 (Ex1) of the 67 exons containing huntingtin gene. Background
- 3. Model for cellular pathogenesis in Huntington's disease. The molecular chaperones Hsp70 and Hsp40 promote the folding of newly synthesized huntingtin (htt) into a native structure Nucleus Cytoplasm
- 4. Superoxide anion Hydrogen peroxide e- e- e- 10-10 M 10-6-7 M O2 O2- H2O2 OHo H2O2 e- 10-5 M Inflammation NADPH oxidases Respiration Fenton chemistry Fe++ ,Cu++ Radiations ProteinsLipids Hydroxyl radical Nucleic acids RNA DNA Cell death Diseases Aging
- 5. Hsp70 + Hsp40/Hdj-1 expression reduce the size of Huntingtin inclusion bodies. Hsp27 (small heat shock protein) is less effective Hsps and NAC (N-Acetylcysteine) could : Reduces ROS/free radical production in 72Q expressing cell Reduces Nitrite Oxyde (NO) level in 72Q expressing cell Reduces Iron (Fe2+ ) intracelular level Maintain the mitochondrial membrane potential in 72Q expressing cell HE oxydation in 72Q expressing cell Protein carbonyl oxidation in 72Q expressing cell Restore partially Proteasome in 72Q and 103Q expressing cell (caspase like activity) Wyttenbach et al (Human Mol. Genet)Wyttenbach et al (Human Mol. Genet) Firdaus et.al (FEBS)Firdaus et.al (FEBS) Cellular model : transient expression of mutated huntingtin exon 1 (HttEx1-polyQ) (fused or not to EGFP) in 103Q expressing cell
- 6. HE oxidation is proportional to polyQ extension size and is not cell specific HE oxidation is proportional to polyQ extension size and is not cell specific
- 7. Hsp70-Hsp40 decrease HE oxidation in HttEx1-72Q granules by reducing the size of the aggregates Hsp70-Hsp40 decrease HE oxidation in HttEx1-72Q granules by reducing the size of the aggregates
- 9. Superoxide anion Hydrogen peroxide e- e- e- 10-10 M 10-6-7 M O2 O2- H2O2 OHo H2Oe- 10-5 M Inflammation NADPH oxidases Respiration Fenton chemistry Fe++ ,Cu++ Radiations ProteinsLipids Hydroxyl radical Nucleic acids RNA DNA Cell death Diseases Aging Fe 2+ + H2O2 Fe 3+ + OH- + OH° Fe 3+ + O2 - ° Fe2+ + O2 H2O2 + O2 - ° Fe2+/ Fe3+ + OH- + OH° + O2 Iron reaction implicated in OHo formation
- 10. Deferroxamine decreasesDeferroxamine decreases ROS formation, the size and the oxidationROS formation, the size and the oxidation of Huntingtin inclusionsof Huntingtin inclusions Scale bar: 20µm COS cell PC12 cell Free radical level
- 11. Proteasome unable to degrade polyQ If >35-38 (toxic) Cells respond by inducing aggregation of HttEx1-polyQ (>35-38 (toxic) HttEx1-PolyQ CAG repeat HspHsp Aggregates not oxidized Autophagy If Fe2+ normal Tight regulation of iron level Autophagy inhibited Oxidation of proteins CellDeath ROS Oxidized of aggregates Caspase activation Fe2+ dependent If Fe2+ >>?
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- 16. WB: Cortex and Hippocampal Probed using synaptosome protein markers PSD-95 NR2B Synaptotagmin Synaptophysin VAchT Gap-43 SNAP-25 Research Part III (b)
- 17. Techniques ExpertiseTechniques Expertise Mouse/Rat Primary Embryonic Neuronal : Cortex,Mouse/Rat Primary Embryonic Neuronal : Cortex, Hippocampus,Astrocytes,Glial and Neuronal Cells CulturesHippocampus,Astrocytes,Glial and Neuronal Cells Cultures Cell Lines: PC12,Mice Neuroblastoma,COS,HelaCell Lines: PC12,Mice Neuroblastoma,COS,Hela SDS PAGE/Western Blot/oxyblot: Protein oxydationSDS PAGE/Western Blot/oxyblot: Protein oxydation Flow Cytometry: ROS production , Mitochondria PotentialFlow Cytometry: ROS production , Mitochondria Potential membranemembrane Confocal Microscopy Imaging in vivo: ROS productionConfocal Microscopy Imaging in vivo: ROS production Electron Microscopy Imaging:protein aggregates,Mitochondria andElectron Microscopy Imaging:protein aggregates,Mitochondria and Golgi morphology structure,Golgi morphology structure, Cryostat Brain Tissue SectioningCryostat Brain Tissue Sectioning Synaptosome Preparation: Percol GradientSynaptosome Preparation: Percol Gradient Immunohistochemistry and Immunocytochemistry,Tissue SectioningImmunohistochemistry and Immunocytochemistry,Tissue Sectioning