ABNORMAL REDOX SYSTEM IN AUTISM

Ved Chauhan

Head, Cellular Neurochemistry Laboratory

NYS Institute for Basic Research in Developmental Disabilities, Staten Island, New York

Autism One, 2009

AUTISM

Severe neurodevelopmental disorder in children

Onset before the age of 3 years

Affects 1 in 150 children

Characterized by

- impaired social interaction

- delayed speech development

- limited verbal communication

- stereotyped and repetitive behavior patterns

- abnormal eye contact

PERVASIVE DEVELOPMENTAL DISORDERS (PDD)

Autism

  Asperger’s disorder (not associated with language delay or general intellectual impairments)

  Childhood disintegrative disorder

  Rett’s disorder

  PDD – not otherwise specified

 

DIAGNOSTIC TESTS FOR AUTISM

Behaviorally defined disorder

  - Autism Diagnostic Interview Revised (ADI-R) Criteria

- Autism Diagnostic Observation Schedule (ADOS) Criteria

  Severity of autism

  - Childhood Autism Rating Scale (CARS)

- Pervasive Developmental Disorder Behavior Inventory (PDDBI) Scale

No biochemical or genetic test

GENETICS OF AUTISM

Polygenetic disorder with involvement of genes mainly on chromosome 7, 15 and 16

Twin studies: high concordance of ~ 90 % among identical twins as compared to ~5 % for fraternal twins and other siblings

Males are 3-4 times more commonly affected than females

ENVIRONMENTAL FACTORS IN AUTISM

Thalidomide, Valproic acid

Heavy metals (lead, mercury)

Bisphenol A

Air pollutants

Chemicals and toxins

Pathogenic bacteria

Viral infection

BIOCHEMICAL ABNORMALITIES IN AUTISM

  Increased blood levels of serotonin (neurotransmitter)

   Increased oxidative stress

   Abnormalities in membrane structure and function

Aberrant signal transduction

OXIDATIVE STRESS IN NEUROLOGICAL DISEASES

Alzheimer’s disease

Down’s syndrome

Parkinson disease

Schizophrenia

Under normal conditions, a dynamic equilibrium exists between the production of reactive oxygen species (ROS) and the antioxidant capacity of the cell.

Oxidative stress and injury to cells occur when ROS generation overpowers the biochemical defense mechanism of the cell to neutralize and eliminate ROS. These ROS are highly toxic and react with lipids, proteins and nucleic acids, and lead to impaired cell functions and cell death .

Chauhan and Chauhan, Pathophysiology 13 (2006) 171–181

Potential mechanism of oxidative stress and mitochondrial abnormalities in autism

INCREASED PRO-OXIDANTS DECREASED ANTI-OXIDANTS Endogenous Exogenous (Environmental factors)

NO Xanthine oxidase Homocysteine

Heavy metals (Hg, Pb) Thalidomide, Valproic

acid, Retinoic acid Air pollutants Chemicals (BPA) and Toxins Pathogenic bacteria Viral infection

Production of free radicals

Lipid peroxidation Protein oxidation DNA oxidation

OXIDATIVE STRESS IN AUTISM

Mitochondrial damage Impaired energy production Increased excitotoxicity

Antioxidant enzymes (SOD, GPx, catalase)

Ceruloplasmin Transferrin Abnormal Cu/Fe

metabolism

Glutathione

Genetic factors

Lipid peroxidation reflects a chain reaction between polyunsaturated fatty acids and ROS providing a continuous supply of free radicals. It results in the formation of lipid peroxides and hydrocarbon polymers that are highly toxic to the cell, and leads to loss of membrane functions and integrity.

LIPID PEROXIDATION

MalondialdehydMalondialdehydee

Malondialdehyde (MDA) is an end product of peroxidation of polyunsaturated fatty acids, and is a marker of lipid peroxidation.

CONTROLS

Developmentally normal (non-autistic) siblings

 

Variables such as race, diet, socio-economic status and genetic background would be similar between normal siblings and autistic children

Autism* Siblings Autism Siblings0.0

0.1

0.2

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0.7

Same sex Different sex

Pla

sma

MD

A (n

mo

le/m

l)

INCREASED LIPID PEROXIDATION IN AUTISM

Age (Years)(Mean S.E.)

Plasma MDA (nmol / ml)(Mean S.E.)

Autism 4.4 0.3 0.497 0.025*,

Siblings 6.0 0.9 0.396 0.019

Increased MDA in 87% autism as compared to normal siblings

* p < 0.005, paired t-test

p < 0.005, unpaired t-test

Antioxidant Defense MechanismsAntioxidant Defense Mechanisms

Enzymatic antioxidants

- Superoxide dismutase (SOD)

- Glutathione peroxidase (GSH-Px)

- Catalase (CAT)

Non-enzymatic antioxidants

- Glutathione, -tocopherol, ascorbic acid

- Transport & Storage proteins

(Transferrin, Ferritin, Ceruloplasmin)

No. of subjects

Age (Years) Transferrin(mg / ml)

Ceruloplasmin(mg / ml)

Autism 19 6.0 0.45 2.456 0.664a, b 0.2996 0.0138c

Siblings 19 6.8 0.87 2.699 0.093 0.3296 0.0182

Reduced transferrin levels in 16 / 19 (84 %) of autism

Reduced ceruloplasmin levels in 13 / 19 (68 %) of autism

a p < 0.005, paired t-test

b p < 0.05, unpaired t-test

c p < 0.02, paired t-test

REDUCED SERUM TRANSFERRIN & CERULOPLASMIN LEVELS IN AUTISM

These results suggest abnormal iron and copper metabolism in autism

RELATIONSHIP BETWEEN CERULOPLASMIN / TRANSFERRIN LEVELS AND LOST ACQUIRED LANGUAGE SKILLS IN AUTISM

Reduced ceruloplasmin / transferrin levels were observed most strongly in children who had shown a loss of previously acquired language skills

Children with autism who had not lost language skills had ceruloplasmin / transferrin levels similar to that seen in the normal siblings

OTHER STUDIES ON OXIDATIVE STRESS IN AUTISM

• Increased TBA-reactive substances in erythrocytes (Zoroglu et al. 2004).

• Increased excretion of 8-isoprostane-F2 alpha in the urine (Ming et al. 2005).

• Increased NO levels in RBCs (Sogut et al. 2005).

• Increased plasma levels of nitrites/nitrates (Sweeten et al. 2004).

• Elevated cerebellar 3-nitrotyrosine levels (Sajdel-Sulkowska et al. 2008).

• Increased density of lipofuscin (matrix of oxidized lipid and cross-linked protein) in language-related cortical brain areas in autism (Lopez-Hurtado, and Prieto, 2008).

• Increased levels of lipid-derived oxidative proteins modifications in autism (Zhu et al., 2008).

Review

Oxidative stress in autism

Abha Chauhan,* and Ved Chauhan

NYS Institute for Basic research in Developmental Disabilities, Staten Island, NY, 10314

Pathophysiology 13 (2006) 171 - 181

Special Issue On

AUTISM SPECTRUM DISORDERS

American Journal of Biochemistry and Biotechnology, Vol. 4, No. 2, 2008

Editor:

Abha Chauhan, Ph.D.

Associate Editors:

Ved Chauhan, Ph.D.

George Perry, Ph.D.

EFFECT OF OXIDATIVE STRESSEFFECT OF OXIDATIVE STRESS

Increased lipid peroxidation

Cell membrane damages

Alterations in membrane fluidity and permeability

Oxidative changes in proteins

Cytotoxicity

Damage to mitochondrial and nuclear DNA

Enzyme modification

Cell death

INCREASED LIPID PEROXIDATION IN THE CEREBELLUM AND TEMPORAL CORTEX FROM AUTISM SUBJECTS

MDA levels were significantly increased in the cerebellum by 124%, and in the temporal cortex by 256% in autism as compared to control subjects.

Chauhan et al. J. Neurochem. 108, Suppl. 1, 33 (2009)

Cerebellum Temporal cortex

Mitochondrial abnormalities in the lymphoblasts from autism

Chauhan et al. J. Neurochem. 108, Suppl. 1, 33 (2009)

Energy metabolism in the cell. Glucose is prime source of energy in the cell. Acetyl CoA is produced from glucose, amino acids and fatty acids. Acetyl CoA enters TCA cycle (Fig. B) and provides NADH (reduced electron carrier) for complex I of electron transport chain (ETC), and succinate for complex II (Fig. A). ETC produces proton gradient (membrane potential) that eventually leads to ATP production.

B

A

Mitochondria

Involvement of oxidative stress and environmental factors in mitochondrial dysfunctions

Mitochondrial dysfunction may result in inflammation, decreased mitochondrial membrane potential and altered energy metabolism.

Oxidative stress

Mitochondrial dysfunctions

Altered membrane potential

Altered energy metabolism

Environmental factors

Inflammation

Oxidative stress

Mitochondrial dysfunctions

Altered membrane potential

Altered energy metabolism

Environmental factors

Inflammation

DHR 123 is an oxidation-sensitive lipophilic dye that enters the cell, and fluoresces when it is oxidized by ROS to rhodamine 123.

Mitochondrial ROS levels were significantly higher in autistic lymphoblasts as compared to control lymphoblasts.

C ontrol Autism0

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Mitochondrial ROS in lymphoblasts from autism and control subjects by dihydrorhodamine 123 fluorescence assay

Rh 123, a cell-permeable cationic dye, preferentially partitions into mitochondria because of highly negative MMP.

Mitochondrial membrane potential was significantly lower in autistic lymphoblasts as compared to control lymphoblasts.

C ontrol Autism0

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MITOCHONDRIAL MEMBRANE POTENTIAL (MMP) IN LYMPHOBLASTS FROM AUTISM AND CONTROL SUBJECTS BY

RHODAMINE (RH) 123 FLUORESCENCE ASSAY

JC-1 exists as a green fluorescent monomer at lower MMP and as red fluorescent aggregates at higher MMP.

Mitochondrial membrane potential (Red / green fluorescence ratio ) was significantly lower in autistic lymphoblasts than in control lymphoblasts.

C ontrol Autism0.0

2.5

5.0

7.5

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/gre

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rat

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MITOCHONDRIAL MEMBRANE POTENTIAL IN LYMPHOBLASTS FROM AUTISM AND CONTROL SUBJECTS BY JC-1 FLUORESCENCE ASSAY

Autism ControlJC-1 exists as a green fluorescence monomer at lower membrane potential and as a red fluorescence dimer at higher membrane potentials. Autistic lymphoblasts shows lower membrane potential (more green) than in control lymbhoblasts (more red).

Confocal microscopic analysis of JC-1 showing decreased mitochondrial membrane potential in autistic lymphoblasts

Schematic depiction of potential mechanisms that may mediate neuronal dysfunction and clinical symptoms in autism. (Reproduced, in part, from Chauhan, A. and Chauhan, V. Pathophysiology 2006: 13, 171-181).

Oxidative stress & Mitochondrial dysfunction

Membrane lipid abnormalities

Neuronal membrane dysfunction

Decreased prostaglandin production

Cell death

Decreased synaptic efficiency

Impaired serotonin receptor functions

Alte red immune response

Increased inflammatory response

Impaired neuronal development

Impaired energy production

Increased excitotocity

Clinical symptoms of autism

Pathogenesis of autism

Abnormal signal transduction

Genetic factors Environmental factors Increased endogenous pro- oxidants Decreased endogenous anti- oxidants

Membrane abnormalities in autism

Phospholipids in the membrane

Phosphatidylcholine (PC)

Phosphatidylethanolamine (PE)

Phosphatidylserine (PS)Phosphatidylinositol (PI) Sphingomyelin (SPG)

 

 

PE and PS ratio of erythrocytePE and PS ratio of erythrocyte

AutismAutism Normal siblingsNormal siblings

0.85 0.85 0.198* 0.198* 1.42 1.42 0.106 0.106

COMPOSITION OF PHOSPHOLIPIDS IN ERYTHROCYTES MEMBRANES OF CHILDREN WITH AUTISM AND THEIR NONAUTISTIC SIBLINGS

Phospholipid Phospholipid fractions fractions

Phospholipid (Phospholipid (g/mg protein)g/mg protein)

AutismAutism

(N = 8)(N = 8)

Non-autistic Non-autistic siblingssiblings

(N = 8)(N = 8)

PEPE 5.12 5.12 0.54*0.54* 6.00 6.00 0.630.63

PCPC 6.40 6.40 0.370.37 6.60 6.60 0.400.40

SPGSPG 5.29 5.29 0.460.46 5.26 5.26 0.460.46

PI + PSPI + PS 5.89 5.89 0.710.71 5.26 5.26 0.460.46

● Levels of PE are decreased and that of PS are increased in the erythrocyte membrane of children with autism.

● Ratio of membrane PE/PS is decreased in autism as compared to control subjects.

Chauhan et al. Life Sci. 74, 1635-1646 (2004)

Trinitrobenzene sulfonic acid (TNBS) reacts with amine-containing molecules such as PE and PS

0 25 50 75 100 1250.0

0.1

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0.8PS-TNBSPE-TNBS

Concentration of lipids (nmol)

Ab

sorb

ance

at

410

nm

AB

C

A: Wavelength scans of PE-TNBS (dotted line) and PS-TNBS (solid line).B: Wavelength scan of plasma lipid-TNBS. C: Standard curves of PS and PE as measured by TNBS assay

Chauhan et al. Life Sci. 74, 1635-1646 (2004)

Autism Siblings0.000.010.020.030.040.050.060.070.080.090.100.110.120.130.140.150.160.170.180.190.200.210.220.230.240.250.260.270.280.290.300.310.320.33

Ab

sorb

ance

at 4

10 n

m

INCREASED AMINOGLYCEROPHOSPHOLIPIDS LEVELS IN PLASMA OF CHILDREN WITH AUTISM

Mean SE 0.2022 0.021 0.1575 0.017

Autism Siblings

Levels of ceruloplasmin (copper-binding protein) are decreased in autism

Chauhan et al. (2004) Life Sci. 75, 2539-2549

PE

PC

SPG

PS + PI

  

Lipids Lipids + Cu2+

COPPER DECREASES THE LEVELS OF PHOSPHATIDYLETHANOLAMINE IN THE LYMPHOBLASTS

Thin layer chromatogram

LipidsLipids Lipids + CuLipids + Cu2+2+

PE (0.56 PE (0.56 g)g) PE (0.08 PE (0.08 g)g)

● PE is oxidized in the presence of copper.

Control Copper Iron Zinc Calcium Cadmium0

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*

* *

CuCl2 [M]

% e

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E o

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n0 1 2 3 4 5 6 7 8 9

0

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% e

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Chauhan et al. Am. J. Biochem. Biotech. 4:95-100 (2008).

Effect of metal cations on the oxidation of PE in the lymphoblasts

● Among the metal cations, only copper oxidized PE

● Copper-mediated oxidation of PE was dependent on copper concentration and incubation time period.

Effect of copper on the PE of lymphoblasts from autism and control subjects

No

co

pp

er

2+M

Cu

20

0

2+M

Cu

4

00

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co

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Cu

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40

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a

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C ontro l Autism

%

efff

ect

of

cop

per

on

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of

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in

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ph

ob

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s

Copper oxidizes more PE in the lymphoblasts from autism than from control

Copper oxidizes both plasmalogenic and non-plasmalogenic PE equally.

Phosphatidylethanolamine:

C1 & C2- Acyl groups (Non-plasmalogenic)

C1- O-alkenyl group (plasmalogen), C2-acyl group (Plasmalogenic)

C1

C2

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*****

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E(t

ota

l, d

iac

yl P

E a

nd

alk

en

yl P

E)

Copper-mediated oxidation of PE-plasmalogen and non-plasmalogenic PE

Copper oxidizes both plasmalogenic and non-plasmalogenic PE

Biological membrane

● Hydrophobic core of membrane is maintained by fatty acid chains of phospholipids.● The movement of fatty acids provides the fluid environment. ● Unsaturated fatty acids enhance membrane fluidity. ● Peroxidation of lipids decreases membrane fluidity.

Age (Years)Age (Years)

(Mean (Mean S.E.) S.E.)

DPH Fluorescence DPH Fluorescence PolarizationPolarization

(Mean (Mean S.E.) S.E.)

Autism (N = 10)Autism (N = 10) 6.09 6.09 0.38 0.38 0.2225 0.2225 0.0045* 0.0045*

Siblings (N =16)Siblings (N =16) 6.56 6.56 1.08 1.08 0.2077 0.2077 0.0026 0.0026

DECREASED MEMBRANE FLUIDITY IN AUTISM

* p < 0.015, unpaired t-test

Autism Siblings0.18

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0.23

0.24

0.25D

PH

Ste

ady

Sta

teF

luo

resc

ence

Po

lari

zati

on Membrane fluidity is inversely

proportional to DPH fluorescence polarization.

Chauhan et al. J. Neurochem. 108, Suppl. 1, 33 (2009)

RELATIONSHIP BETWEEN MEMBRANE FLUIDITY AND SEVERITY OF AUTISM

Correlation coefficient: r = 0.72, p < 0.02

Membrane fluidity decreases with severity of autism

Maintenance of optimum membrane fluidity is critical to biological functions

It has a marked effect on membrane properties.

It modulates the activity of membrane - bound enzymes, ion channels and receptors.

The activity of integral membrane proteins are markedly affected by the physical state of the lipids in which they are embedded.

The phospholipids make up the bulk of all internal and external neuronal membranes. Alteration in membrane lipids can result in defective membrane functions and therefore, may have wide impact on learning and behavior.

Phosphatidylcholine

LysophosphatidylcholineArachidonic acid

Phospholipase A2

Action of phospholipase A2 on phospholipids

Unsaturated fatty acids and autism

•Physical state of the membrane affects the functions of membrane- associated proteins, e.g., unsaturated fatty acids of neuronal phospholipid affect functions such as neuronal transmission, ion channels, enzyme regulation & gene expression (Young and Conquer, 2005), insulin receptors in fluid membrane (Neufeld and Corbo, 1984).

• -9 fatty acids in autism (Bu et al., 2006), -3 fatty acids in Attention Deficit Disorder, Alzheimer’s disease, Schizophrenia and depression (Young and Conquer, 2005).

• Dietary -3 supplementation affects the behavior abnormalities: hyperactivity and stereotypic features (Amminger et al.,2007).

Polyunsaturated fatty acids are decreased in the erythrocyte membranes of autism as compared to normal control (Bell et al. 2000, 2004).

Chromosomal linkage studies in autism points to a locus where PLA2 gene is located (Lamb et al. 2000).

Bell et al. (2004) reported that PLA2 activity is increased in

the erythrocytes of autism as compared to controls.

Increased levels of PLA2 in the erythrocytes of patients with

schizophrenia (Ward et al. 2000) and dyslexia (MacDonell et al. 2000).

Phospholipase A2 and autism

Lymphoblasts PLA2 activity (cpm/4h)

Autism 8634 1704

Control 3061 1437

 

Increased PLA2 activity in lymphoblasts from autism

Activities of Ca2+/Mg2+-ATPase, Na+/K+-ATPase, protein kinase C and protein kinase A in autism

Autism Siblings C ontrol0

10

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Ca

2+/M

g2+

AT

Pas

e ac

tivity

(g

ph

osp

hru

s / m

g p

rote

in /

min

)

Increased Ca2+-ATPase activity in the lymphoblasts of autistic subjects

Chauhan et al. J. Neurochem. 108, Suppl. 1, 33 (2009)

C ontrol Autism80

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Ph

osp

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rele

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(

g)/

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/hIncreased activities of Ca2+-ATPase and Na+/K+ ATPase in the cerebellum of autistic subjects

Ca2+-ATPase

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)/m

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Na+/K+-ATPase

Autism C ontrol0.0

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/mg

pro

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Decreased activity of Protein kinase C (PKC) in the lymphoblasts of autism

Cytosolic Membrane-bound

Activity of PKC in the cytosol and membrane fraction of lymphoblasts from autism are decreased as compared to controls

Autism C ontrol0

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40M

emb

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rote

in K

inas

e A

(Op

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pro

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)

Increased Protein kinase A activity in the lymphoblasts of autism

Membrane-associated proteins and their involvement in the etiology of autism

Pten controls development of neuronal and synaptic function (Fraser et al. 2008).

Pten mutations have been reported in autistic individuals with macrocephaly (Butler et al. 2005; Goffin et al. 2001; Zori et al. 1998).

Decreased levels of Akt are associated with schizophrenia (Emamian et al. 2004), and in individuals with TSC mutations exhibiting central nervous system disorders including autism (Wiznitzer 2004).

Reelin plays a pivotal role in migration of neurons and in the development of neuronal connections.

Dysregulation of reelin has been reported in the brain of individuals with autism (Fatemi et al. 2001, 2005; Serajee et al. 2006)

Neuroligins are postsynaptic transmembrane proteins that bind to neurexins.

Neuroligins maintain the functionality of synaptic circuitry.

Both neurxins and neuroligins have been identified as candidate genes for autism.

Serotonin plays role in anger, aggression, mood, sleep, appetite, and metabolism.

Hyperserotonemia is reported in platelets of autistic subjects.

Serotonin transporter (SERT)-binding capacity is disturbed in autism (Makkonen et al. 2008; McDougle 2008).

CONCLUSIONS      Lipid peroxidation is increased in the plasma of autistic children as compared to their developmentally normal non-autistic siblings.

       The levels of transferrin (iron-transport protein) and ceruloplasmin (copper-transport protein), the major antioxidant proteins, are decreased in the serum of children with autism as compared to their normal siblings. These effects were seen most strongly in autistic children who had shown a loss of previously acquired language skills.

      Lipid peroxidation is increased in the cerebellum and temporal cortex from autism as compared to control subjects.

The levels of free radicals i.e. ROS in the mitochondria are significantly higher in the autism lymphoblasts as compared to control lymphoblasts.

The mitochondrial membrane potential is significantly decreased in autism lymphoblasts as compared to control lymphoblasts.

    Levels of aminoglycerophospholipids are altered in the plasma and Levels of aminoglycerophospholipids are altered in the plasma and erythrocyte membrane of autism.erythrocyte membrane of autism.

   Levels of ceruloplasmin are decreased in the plasma of autism.Levels of ceruloplasmin are decreased in the plasma of autism.

   Decreased levels of PE in the membrane could be due to copper- mediated oxidation of PE in autism.

  Copper-mediated oxidation of PE is higher in lymphoblasts from autistic subjects as compared to control subjects.

    Fluidity of the membrane is decreased in autism.Fluidity of the membrane is decreased in autism.

    Activity of phospholipase AActivity of phospholipase A22 is increased in the lymphoblasts of is increased in the lymphoblasts of

autism.autism.

    Activity of CaActivity of Ca2+2+-ATPase is increased in the lymphoblasts and brains of -ATPase is increased in the lymphoblasts and brains of autism.autism.

    Activity of NaActivity of Na++/K/K++-ATPase is increased in the brains of autism.-ATPase is increased in the brains of autism.

   Activities of membrane- bound and cytosolic PKC are decreased in the Activities of membrane- bound and cytosolic PKC are decreased in the lymphoblasts of autism.lymphoblasts of autism.

    Activity of PKA is increased in the lymphoblasts of autism.Activity of PKA is increased in the lymphoblasts of autism.

These results suggest that mitochondrial dysfunction, oxidative stress, membrane abnormalities and aberrant cell signaling may contribute to pathophysiology of autism.

Acknowledgements

SPONSORS: New York State Office of Mental Retardation and Developmental Disabilities, NYS Legislative Funds for Autism Research, Autism Speaks, Autism Research Institute, and Department of Defense

Lina Ji

Abha Chauhan Balu MuthaiyahEssa Mohamed

Ira Cohen Maripez Gonzalez

Ed Jenkins

Jerzy Wegiel

Ted Brown