Presentation on theme: "“How Genetic and Environmental Factors Conspire to Cause Autism”"— Presentation transcript:
1 “How Genetic and Environmental Factors Conspire to Cause Autism” Richard Deth, PhDNortheastern UniversityBoston, MA
2 Overview Sulfur metabolism and evolution Oxidative stress as an adaptive responseMethionine synthase in autismD4 dopamine receptor-mediated PLMNeuronal synchrony and attention
3 Earliest life appears to have arisen at hydrothermal vents emitting hydrogen sulfide and other gases at high temperature and pressureH2SH2O
4 Evolution 3 Billion Years Primates 85 million yrs Humans OriginofLife3 Billion YearsMethaneHydrogen sulfideAmmoniaCarbon dioxideNo Oxygen!!Anaerobic LifeAerobic LifeOxygen(electrophile)
5 Primordial Synthesis of Cysteine From Volcanic GasesMethane CH3Hydrogen sulfide H2SAmmonia NH3Carbon dioxide CO2NH2CHCOOHCH2SHCysteine
6 Cysteine can function as an antioxidant Two AntioxidantReducing EquivalentsNH2CHCOOHCH2SNH2CHCOOHCH2SHNH2CHCOOHCH2SH++ 2 H+Two CysteinesCysteine Disulfide
7 = Evolution = Adaptation to threat of oxidation O2 O2 Genetic Mutation NovelAntioxidantAdaptation=Adaptive features ofsulfur metabolism
8 Metabolic Adaptations to an Oxygen Environment Evolution =Metabolic Adaptationsto an Oxygen EnvironmentFigure from Paul G. FalkowskiScience (2006)
9 EVOLUTION = LAYER UPON LAYER OF USEFUL ADAPTIVE RESPONSES TO ENVIRONMENTAL THREATS
10 The ability to controloxidation is at thecore of evolutionEach addition isstrengthened becauseit builds on thesolid core alreadyin place.
11 LANGUAGE SOCIAL SKILLS New capabilities are added in the context of the particular environmentin which they are useful and offer a selective advantage.Recently added capabilities are the most vulnerable to loss when andif there is a significant changes in the environment.Humans cognitive abilities are particularly vulnerable.LANGUAGESOCIAL SKILLS
23 Thimerosal decreases methylcobalamin levels to a much greater extent than GSH levelsin SH-SY5Y human neuronal cellsGSH levelsThimerosal = 1 Mfor 60 minMethylcobalamin levelsThimerosal = 0.1 Mfor 60 min
26 6-Phospho-gluconolactone DETERMINANTS OF THE GSH/GSSH RATIOCellular uptakeTranssulfurationCysteineGlutamateGlucoseγ-GlutamylcysteineThimerosalHexokinaseGlycineGlutaredoxin(reduced)GSHGlucose-6-PhosphateNADPHGSSGReductaseROS InactivationDetoxification(e.g. GPx)G6PDGlutaredoxin(oxidized)NADP+GSSG6-Phospho-gluconolactone
28 Site of alternative splicing by mRNA-specific adenosine deaminase Alternative Splicing of MS Pre-mRNACap DomainPresentCap Domain Exons 19-21HCYFOLCOBSAMSite of alternative splicing bymRNA-specific adenosine deaminaseCap DomainAbsentPre-mRNAmRNA
29 SAM domain is present in MS mRNA from human cortex, but CAP Domain is absent 80 year old subjectHCYFOLCAPCOBSAM
30 SAM domain is present in MS mRNA from human cortex, but CAP Domain is absent HCYFOLCAPCOBSAMControl Subject: Age 80 yrs30
31 CAP Domain is present in MS mRNA from 24 y.o. subject HCYFOLCAPCOBSAMPartial splicing product
32 CAP Domain is present in MS mRNA from 24 y.o. subject Control Subject: Age 24 yrsHCYFOLCAPCOBSAM32
33 Human Cortex Late Alzheimer’s Cap Domain is Absent from Methionine Synthase mRNA in All Elderly Subjects (> 70 yrs)Human Cortex ControlsHuman Cortex Early Alzheimer’sHuman Cortex Late Alzheimer’s
34 mRNA for methionine synthase is 2-3 fold lower in cortex of autistic subjectsas compared to age-matched controls
35 Representative comparison of methionine synthase cap domain mRNA for autistic and control subjects35
36 No age-dependent trend was observed for either Cobalamin or Cap domains inindividuals 30 years or younger
37 Conclusion:There are lower amounts of mRNA formethionine synthase in the cortex ofautistic subjects and levels of theenzyme are also likely to be lower.Lower expression levels may reflect anadaptation to oxidative stress.This implies an impaired capacity formethylation, including D4 dopaminereceptor-mediated phospholipid methylation.
38 Levels of cystathionine are markedly higher in human cortex than in other speciesTallan HH, Moore S, Stein WH. L-cystathionine in human brain. J Biol Chem Feb;230(2):
45 Why put neurons at higher risk of oxidative stress? One possible explanation:Oxidative stress stops cells from dividing. Neuronshave to avoid cell division, otherwise they would loseall their connections and all of their information value.Thus neurons must balance on the precarious knife-edgeof oxidative stress.
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