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University Hospital of the Saarland

Department of Clinical Chemistry and Laboratory Medicine. University Hospital of the Saarland. Australian Association of Clinical Biochemists Talk, Sydney, April 20th. Role of Phosphorylation and Methylation in Neurodegenerative Diseases (Alzheimer and Parkinson). Wolfgang Herrmann.

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University Hospital of the Saarland

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  1. Department of Clinical Chemistry and Laboratory Medicine University Hospital of the Saarland

  2. Australian Association of Clinical Biochemists Talk, Sydney, April 20th Role of Phosphorylation and Methylation in Neurodegenerative Diseases (Alzheimer and Parkinson) Wolfgang Herrmann Department of Clinical Chemistry and Laborotory Medicine Medical School, Saarland University, Germany

  3. 7,2 > 65 Prevalence of dementia according to age (Germany, 2004) 50 34,6 40 23,9 30 Prevalence 13,3 20 6,0 2,8 1,2 10 0 65-69 70-74 75-79 80-84 85-89 > 90 Deutsche Alzheimer Gesellschaft

  4. Risk factors and Hypotheses for Dementia Risk factors Our hypothesis: Brain hypomethylation is related to phosphorylated tau, -amyloid proteins and α-Synuclein non-genetic genetic Hypotheses Homocysteine/methylation -amyloid hypothesis Tau Protein Oxidative stress Cholesterol ApoE4, 3 Down syndrome Unknown factors ??

  5. Transmethylation SAM SAH Methyl group metabolism in the brain Remethylation CH3 SAM Methionine - THF B12 MS DNA hypomethylation  ↑ gene expression (PSI)  ↑ -amyloid Protein hypomethylation: ↓ SAM  ↓ PP2A methylation  ↑ P-tau Phospholipids; ↓ SAM ↑ PE/PC  ↓ phosphadic acid  ↓ diacylglycine  ↓ PKC  ↑ APP hydrolysis  ↑ -amyloid α-Synuclein Neurotransmitters SAH 5-MTHF SAH- hydrolase Homocysteine CBS Cystathionine Cystathionase Cysteine

  6. Tau; important during normal metabolism Tau hyper-phosphorylation, glycation or structural modifications result in self-aggregation impaired axonal transport, synaptic dysfunction axonal degeneration/ disconnection Diseased neuron

  7. over-active kinases + P P -ser199 Self-aggregation P P -thr181 assembly into paired helical filament P P - Phospho-Tau Hyperphosphorylated Hypo-active phosphatases Neuron degeneration Tau Hyperphosphorylation & Neural Degeneration Kinases Phosphatase PP2A Tau

  8. B; regulatory subunit SAM SAH B A A CH3 A B C C C Mtase* Active PP2A Inactive PP2A Pi  Tau-P Leu309 Tau-P Tau  SAM ATP ADP Kinases GSK-3 and CDK5 TPKI/GSK-3beta Self-aggregation Self-aggregation Tangling Tangling Neuron degeneration Neuron degeneration P-Tau; A Link to Methyl Group Metabolism? * Protein phosphatase methyltransferase 1 (PPM1)

  9. 300 R=0.46, p<0.001, n=141 R=0.31, p<0.001 after adjusting for age 200 100 90 80 70 60 Phospho tau protein (181P), ng/l 50 40 30 20 10 4 6 8 10 30 20 40 CSF SAH, nmol/L CSF-P-tau is negatively related to CSF-folate and positively to CSF-SAH 182 patients (multiple sclerosis, stroke, dementia, peripheral neuropathy, others) R=-0.28, p=0.001, n=133 R=-0.18, p=0.048 after adjusting for age 8 9 10 20 30 40 CSF folate, nmol/L Obeid et al., ClinChem 2007

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