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Redox and Methylation in the Gut, Brain and Immune System Part II: Autism-specific Aspects

Redox and Methylation in the Gut, Brain and Immune System Part II: Autism-specific Aspects. Richard Deth, PhD Northeastern University Boston, MA. Overview Methionine synthase in human brain Autism: An epigenetic disorder triggered by oxidative stress

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Redox and Methylation in the Gut, Brain and Immune System Part II: Autism-specific Aspects

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  1. Redox and Methylation in the Gut, Brain and Immune System Part II: Autism-specific Aspects Richard Deth, PhD Northeastern University Boston, MA

  2. Overview • Methionine synthase in human brain • Autism: An epigenetic disorder triggered by • oxidative stress • Gluten and casein-derived opiate peptides • - D4 dopamine receptors, methylation and ADHD

  3. HCY Domain SAM Domain SAM Domain 3 2 1 Cobalamin Cobalamin (vitamin B12) (vitamin B12) Cobalamin Cobalamin Cap Cap 5-Methyl THF Domain Domain Domain Domain Domain Methionine synthase has five domains + cobalamin (Vitamin B12) Domains alternate interacting with cobalamin during turnover

  4. Decrease of Cob domain mRNA with increasing age, 40 subjects 28 weeks of fetal development

  5. Decrease of Cap domain with increasing age, 40 subjects

  6. CAP Domain is present in MS mRNA from 24 y.o. subject FOL SAM HCY CAP COB Deth, unpublished observations

  7. CAP Domain is absent from methioninesynthase mRNA in elderly human cortex 80 year old subject FOL SAM HCY CAP COB Deth, unpublished observations

  8. Age-dependent decrease in the ratio of Cap to Cobalamin mRNA 80 year old subject FOL SAM HCY CAP COB Deth, unpublished observations

  9. In human neuronal cells, MS exists as two molecular weight bands. Both are smaller than the expected full-size molecular weight of 140 kDa. 125 kDa Exons 16-18 are absent 110 kDa Exons 16-20 are absent

  10. Alternative Splicing of MS Pre-mRNA Cap Domain Present Cap Domain Exons 19-21 FOL SAM COB HCY Site of alternative splicing by mRNA-specific adenosine deaminase Cap Domain Absent Pre-mRNA mRNA

  11. 28%↓ 36%↓ 38%↓ Autism is associated with oxidative stress and impaired methylation

  12. Eleven studies showing significantly lower GSH in autism

  13. Oman Autism Collaboration Drs. Mostafa Waly and Yahya Al-Farsi Data from Waly et al. (In Prep)

  14. Data from Waly et al. (In Prep)

  15. Gender differences between autistic subjects in Oman Data from Waly et al. (In Prep)

  16. Folate and B12 Levels are Markedly Lower Data from Waly et al. (In Prep)

  17. Odds of autism decrease with increasing duration of breastfeeding

  18. Thus malnutrition-based autism in Oman shares a similar metabolic profile to autism in the U.S. i.e. Oxidative stress and impaired methylation are fundamental features of autism Data from Waly et al. (In Prep)

  19. mRNA for methionine synthase is 2-3 fold lower in cortex of autistic subjects as compared to age-matched controls

  20. The level of methionine synthase mRNA is reduced by 50% in postmortem brain of autistic subjects vs. age-matched controls

  21. A preliminary qRT-PCR evaluation of redox/methylation-related gene expression In blood-derived RNA of autistic vs. control subjects

  22. THE ROLE OF GUT INFLAMMATION IN AUTISM: GLUTEN AND CASEIN-DERIVED PEPTIDES INHIBIT CYSTEINE UPTAKE

  23. FOOD-DERIVED OPIATE PEPTIDES

  24. A1 casein contains HIS at position 67 and is readily hydrolyzed to BCM7 A2 casein contains PRO at position 67 and is resistant to hydrolysis

  25. IC50 values 62 nM 14 nM 16 nM 4 nM 7.022 nm

  26. Bovine casomorphin 7 decreases cysteine, glutathione, and methionine levels in neuronal cells. Homocysteine and cystathionine levels are increased. • This is consistent with: • 1. Decreased cysteine uptake • 2. Decreased GSH synthesis • 3. Lower activity of methionine • synthase • 4. Increased transsulfuration

  27. Opiate peptides can inhibit cysteine uptake and promote oxidative stress GI Tract Blood Brain GI Blood Epithelial Brain Gluten/Casein Cell Barrier Astrocytes ↓GSH ↓GSH ↓Cystine Cysteine Cysteine ↓Cysteine - ↓Cysteine ( ) Opiate Peptides ↓Cystine ↓Cystine Gluten/Casein ( - ) Opiate Peptides ↓Cysteine ↓GSH Oxidative Stress ↓ Methylation Wheat/Milk Neurons ↓Cysteine ↓Cystine Liver

  28. EAAT3-mediated cysteine/selenocysteine uptake in the terminal ileum EAAT3

  29. Effects of morphine and bovine and human casomorphin-7 peptides on redox/methylation gene expression in human neuronal cells

  30. Autism-associated changes in gene expression in terminal ileum Data from Drs. Steve Walker and Arthur Krigsman

  31. A1 Beta Casein Consumption is correlated with increased risk of juvenile-onset diabetes r = 0.92

  32. Using A1 cow milk formula with hydrolyzed casein lowered autoimmunity and incidence of type I diabetes by ~ 50%

  33. Breast Milk Constituents Can Exert Epigenetic Effects BREAST MILK Casein Growth Factors DHA GI Peptidases Beta Casomorphin Modulation of GI cysteine uptake Systemic availability of cysteine Δ Cellular Redox Status Δ Methylation Status Δ Gene Expression Brain GI Tract Immune System

  34. The GI tract is a critical site for immune cell activation, especially during postnatal development. Decreased cysteine uptake can promote oxidative stress and inflammation, resulting in epigenetic effects which can last throughout life. Postnatal Epigenetic Programming (PEP) Prenatal Epigenetic Programming (PREP)

  35. Opiate peptides are released from gluten and casein by enzymes in the GI tract and regulate cysteine uptake Gluten Casein Autism Autoimmunity (Type 1 diabetes) Opiate Peptides GI Inflammation (celiac disease) ↓Cysteine Uptake ↓ Antioxidant Capacity

  36. Healthy Glial Cells (Astrocytes) Growth Factors Cysteinylglycine Cysteine GSH EAAT3 ( + ) GSCbl GSH GSSG OHCbl PI3-kinase SAM γ-Glutamylcysteine MeCbl Cysteine PARTIALLY BLOCKED IN NEURONAL CELLS Cystathionine Adenosine Adenosine D4SAH D4HCY SAH HCY ( - ) MethylTHF MethylTHF Phospholipid Methylation • >150 • Methylation • Reactons Methionine Synthase THF THF D4SAM D4MET SAM MET ATP PP+Pi ATP PP+Pi Dopamine In neurons, D4 dopamine receptors carry out phospholipid methylation, which requires methionine synthase to supply methyl groups

  37. DOPAMINE –STIMULATED PHOSPHOLIPID METHYLATION DOPAMINE CH3 Methylfolate Methionine Synthase

  38. Structural features of the dopamine D4 receptor Seven repeats are associated with increased risk of ADHD

  39. 2 or 4-repeats 7-repeats Gamma frequency responses are stronger for 7-repeat D4 receptor or 10-repeat dopamine transporter

  40. Dopamine causes an increase in gamma frequency in a patient with Parkinsonism Blue = with dopamine (l-DOPA)

  41. Increased gamma frequency activity in response to a visual task at eight months of age vs. six months Csibra et al.Science290 1582-1585 (2000)

  42. Broca’s area Wernicke’s area

  43. Healthy Glial Cells (Astrocytes) Growth Factors Cysteinylglycine Cysteine GSH EAAT3 ( + ) GSCbl GSH GSSG OHCbl PI3-kinase SAM γ-Glutamylcysteine MeCbl Cysteine PARTIALLY BLOCKED IN NEURONAL CELLS Cystathionine Adenosine Adenosine D4SAH D4HCY SAH HCY ( - ) MethylTHF MethylTHF Phospholipid Methylation • >150 • Methylation • Reactons Methionine Synthase THF THF D4SAM D4MET SAM MET ATP PP+Pi ATP PP+Pi Dopamine In neurons, D4 dopamine receptors carry out phospholipid methylation, which requires methionine synthase to supply methyl groups

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