A Proposed Mechanism for Autoimmune Mediated Motor Dysfunctions, and a Hypothesis for Therapeutic Intervention in Tourette Syndrome, Choreas, Autism, and Attention Deficit Hyperactivity Disorder
A research study involving autoantibodies, PANDAS, autism, anti-brain antibodies, proteomics, choreas, thalamocortical pathways, ADHD, streptococcus and a wonderful research subject who makes her parents proud every day.
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A Proposed Mechanism for Autoimmune Mediated Motor Dysfunctions, and a Hypothesis for Therapeutic Intervention in Tourette Syndrome, Choreas, Autism, and Attention Deficit Hyperactivity Disorder
1. A Proposed Mechanism for Autoimmune Mediated Motor Dysfunctions,
and a Hypothesis for Therapeutic Intervention in Tourette Syndrome,
Choreas, Autism, and Attention Deficit Hyperactivity Disorder
(Keywords – Autism, Glutamate NMDR receptor, NR2B, Nedasin, Neurexin, Neuroligin,
Sydenham's chorea, OCD, tics, PSD-95, thalamocortical pathway)
Richard Wicks
(Former) President
Fortron Bio Science Inc.
Morrisville, NC
Sept. 25, 2000
Copy ___ of 15
dickwicks@nc.rr.com
2. Page 2
Outline
1. Streptococcus – Association with Movement Disorders/Obsessive
Compulsive Disorder (OCD)/Attention Deficit Hyperactivity
Disorder (ADHD)
2. Search for Streptococcal Target Autoantigens
3. Current Study on Proposed Target Autoantigen
4. Nedasin S-form/Synaptic Associated Proteins (SAPs)
5. Association of NE-dlg/SAP102 Proteins with Movement
Disorders/OCD/ADHD and Specific Areas of the Brain
6. Hypothesis – target autoantigen and NMDA NR2B activity in
CSTC motor circuits
7. Evidence in support of hypothesis:
A. Involvement of glutamate and dopamine in movement and
neurobehavioral disorders
B. Parkinson’s Disease
C. Tourette Syndrome
D. Sydenham’s chorea
E. Autism
F. Attention Deficit Hyperactivity Disorder
G. SLE with CNS involvement
8. Glutamate NMDA NR2B Enhancement
9. Acute Post-Streptococcal Glomerulonephritis
10.Nedasin S-form (guanine deaminase activity)
11. Summary
12. Ongoing and Proposed Studies
3. Page 3
Streptococcus – Association with Movement Disorder/OCD/Attention Deficit Disorder
A movement disorder called “St. Vitus’ Dance” was first described in 1686.(1) Now
termed Sydenham’s chorea (SC), it is characterized by frequent adventitious and
uncoordinated movements. SC is a major manifestation of acute rheumatic fever (ARF).
ARF is known to be due to an abnormal susceptibility to group A beta hemolytic
streptococcal infections, which induces antibodies to the streptococcus cell wall that cross
react with and damage heart tissue.(2,3) SC occurs in 20-40% of patients with ARF.(4) It
is usually accompanied by obsessions and compulsions, emotional lability, and
hyperactivity, along with motor dysfunction. The incidence of SC has fallen dramatically
since the 1960’s in parallel with the decline in the incidence of ARF. However, over the
past decade, there has been a resurgence in this disorder, primarily in the United States. (5)
Substantial clinical overlap occurs between SC (choreic symptoms, obsessive compulsive
disorder or OCD, hyperactivity), Tourette’s syndrome (motor tics, OCD, oppositional
behavior), autism (motor tics and stereotypical movements, OCD), and attention deficit
disorder or ADHD (hyperactivity, increased incidence of OCD and oppositional
behavior).(6-13) In SC, the obsessive compulsive symptoms typically begin shortly before
the onset of chorea.(7) In 1976, Husby demonstrated antibodies in the serum of patients
with SC, which cross reacted with human caudate and subthalamic nuclei in the brain. (14)
They further showed a temporal relationship between the presence of these anti-neuronal
antibodies and the choreic symptoms. The antibodies also showed specificity for group
A streptococci, since absorbing the serum with group A streptococcal membranes
abolished the anti-neuronal activity. This reactivity appeared to be an example of the
same molecular mimicry mechanism associated with antibodies to streptococcus which
cross react with heart tissue in acute rheumatic fever.
In 1989, Kiessling noticed an increased incidence of abrupt onset of motor tics in
children after a local group A strep epidemic.(15) They studied children with motor tics,
and also found an increased incidence of antibodies in their serum which reacted with
human brain tissue. These antibodies reacted primarily with the caudate, putamen, and
globus pallidus in the brain.(16) Numerous studies have now shown a correlation between
group A strep infections and antibodies to the basal ganglia area of the brain in Tourette’s
syndrome, SC, OCD, and attention deficit disorder.(8, 17-20) In addition, MRI imaging
studies have documented changes in the size of the basal ganglia in patients which show
a temporal relationship to the brain reactive antibody levels and their symptoms.(21-24)
Treatment of patients with plasmapheresis, IV gamma globulin, or immunosuppressive
doses of prednisone have shown significant reductions in the OC and motor dysfunction
symptoms of some patients, further supporting an immunological basis for these
disorders.(7, 20, 25, 26) An animal model has also provided support for this hypothesis.(27) In
this study, rats were microinfused into the caudate area with serum from patients with
Tourette’s syndrome. The rats developed episodic phonic utterances and stereotypic
dyskinesias, which persisted for several days post-infusion.
4. Page 4
The existence of a syndrome designated PANDAS (pediatric autoimmune
neuropsychiatric disorder associated with streptococcal infections) is still somewhat
controversial. It is not clear whether some of these cases define a narrow subset, or are
indicative of a more generalized etiology for these varied disorders. Indeed, one recent
study suggests that previous reports on the association of streptococcal/brain antibodies
and chronic tic disorders and OCD were confounded by the presence of comorbid
ADHD.(28) This study found a significant correlation between streptococcal antibodies
and ADHD, but not to OCD or chronic tic disorders. In subjects with ADHD or OCD, or
both disorders, higher antibody titers predicted changes in the size of the basal ganglia.
Further studies may clarify the relationship between the streptococcal infection and the
various clinical syndromes.
An additional factor linking streptococcal infections and neuropsychiatric disorders is the
prevalence of the D8/17 marker. In an attempt to discern why the majority of patients
who develop strep throat do not go on to develop ARF, Zabriskie and colleagues
developed a panel of mouse monoclonal antibodies to surface antigens on lymphocytes of
patients with rheumatic fever. A monoclonal antibody reacting with a B cell surface
antigen termed D8/17 was found to discriminate between patients developing rheumatic
fever and chorea, and those who did not.(29) The patients with ARF typically have the
D8/17 marker on 30-40% of their lymphocytes, while patients with strep infections
without ARF have less than 10% reactivity. Family studies have shown the vulnerability
to ARF, and the presence of the D8/17 marker are inherited in a recessive manner.(30)
Expanding on this study, Swedo et.al., studied children with streptococcal induced
PANDAS, and found 85% of the children were D8/17 positive.(31) Two other studies
have shown an increased expression of D8/17 in Tourette’s syndrome (TS), and OCD
patients without a clear streptococcal infection trigger.(32,33) A more recent study looked
at D8/17 expression in autism and found 78% of the patients positive for the marker, with
the degree of D8/17 antigen positivity correlating with the severity of compulsive
behaviors.(34)
Search for Streptococcal Target Autoantigens
Considerable efforts have been made to explore the mechanism of the cardiac damage
found in ARF, with most of the emphasis on the streptococcal M proteins which are the
main virulence factors for group A strep infections.(35) These M proteins have been
found to be similar immunochemically and structurally to a number of human host
autoantigens including myosin,(36-40) tropomyosin,(41) and vimentin.(42) The M5 serotype
of S. pyogenes has most often been associated with rheumatic fever outbreaks.(43) T-cell
clones have been isolated from the affected heart valves of rheumatic fever patients.
These clones have been shown to react with both heart tissue and streptococcal M5
protein, suggesting that these M proteins are crucial to the pathogenesis of ARF.(44) One
region of the streptococcal M5 protein has been reported to be a so-called
“superantigenic” site.(45) It represents amino acid residues 157 to 197 in the published
M5 gene sequence.(46) This superantigenic site contains a 5 amino acid sequence
(QKSKQ), which has previously been reported to react with anti-myosin antibodies in
5. Page 5
patients with ARF.(47) The injection of cardiac myosin has been shown in studies to be
capable of inducing myocarditis in animals.(48,49) A molecular analysis of T cell epitopes
of the M5 protein which react with cardiac myosin has been localized to key regions with
myosin like repeats within the M5 molecule.(50) Numerous other studies have implicated
cardiac myosin as the target autoantigen in rheumatic fever.(51-55)
In 1993, Bronze and Dale published a study which examined the epitopes on
streptococcal M proteins which cross reacted with the antibodies to the brain tissue which
were observed in SC patients.(17) They demonstrated that purified M proteins from type
5, 6, and 19 streptococci induced antibodies in rabbits which cross reacted strongly with
the basal ganglia area of human brain. Using western blot analysis, they showed that
these antibodies reacted with multiple proteins in the brain extracts. With the use of
synthetic peptides, they localized the epitope specificity of the antibodies by
demonstrating inhibition of the binding in the western blot analysis. The epitope alanine-
lysine-glutamate (AKE) was found to represent the common conserved sequence found
in the M5, M6, and M19 proteins which inhibited the binding of the brain reactive
antibodies. The M5 and M6 streptococcal proteins contained either a KLAKE or KIAKE
epitope. This KLAKE epitope (M5 residues 179-183) is contained within the 41 amino
acid region which is presumed to be a superantigenic site for type 5 streptococci. It is
also contiguous with the QKSKQ epitope which was reported to react with anti-myosin
patients in ARF. Serum from a patient with SC also demonstrated strong reactivity to the
brain which was inhibited by a synthetic peptide corresponding to M5 residues 164-197.
Superantigenic site (aa 157-197)
KEQENKETIGTLKKILDETVKDKLAKEQKSKQNIGALKQEL
M5 protein (aa 164-197) TIGTLKKILDETVKDKLAKEQKSKQNIGALKQEL
M6 protein TVKDKIAKEQEST
M19 protein IIDDLDAKEN
Myosin heavy chain DQNCKLAKEKKLL
Previous studies showed that antibodies to M5 residues 164-197 cross reacted with
purified sarcolemmal membranes in human heart, as well as type 5, 6, and 19
streptococci.(56) Since the KLAKE epitope was contained within residues 164-197 of the
M5 protein, they examined these antibodies (which were affinity purified from
sarcolemmal membrane preparations) for brain cross reactivity, and found that they did
indeed produce a binding pattern to brain proteins similar to the M5 protein antiserum.
This indicated that the same epitopes might be responsible for the damage to heart tissue
in ARF patients and the antibody binding to basal ganglia in SC patients.
Current Study on Proposed Target Autoantigen
A study by the author in 1994 demonstrated an antibody in the serum of a patient with
autism (his daughter) which reacted with a 47 kd protein in human brain by Western blot
analysis. No attempt was made to identify the protein due to technological limitations at
that time. Recently, this patient demonstrated an abrupt onset of motor tics, coincident
with an epidemic of strep A infection in her classroom and school. Although a throat
6. Page 6
culture and ASO and Dnase B antibody tests for group A strep were negative, the author
undertook a further investigation due to the extremely sudden onset of tics, and the
previous literature suggesting an association of motor tics with strep infection.
Serum was collected from this patient approximately two weeks after the sudden onset of
motor tics, and a total immunoglobulin fraction isolated and bound to a solid phase
agarose gel. A human brain soluble extract was prepared and incubated with the solid
phase antibody from the patient’s serum. After extensive washing of the column, the
antibody bound proteins were eluted from the column and a concentrated sample of the
eluted proteins run on 2 dimensional (2D) SDS-PAGE electrophoresis. Proteins were
visualized with Coomasie blue staining, and 2D gel spots were identified by the
traditional proteomic method of in-gel trypsin digestion, followed by MALDI-TOF
analysis of the digested peptides and peptide mass fingerprinting and database searching.
Figure 1 shows the pattern of the 2D gel electrophoresis of the antibody bound proteins.
(The proteins at approximately 55 kD and 24 kD represent IgG which was stripped from
the affinity column by the elution buffers).
Figure 1
3.5 pI 10
7. Page 7
The identities of the proteins are listed in Table 1.
TABLE 1 (Proteins Bound by Patient Antibody Column)
Gel Spot Name Accession
Number #
1 Alpha-fodrin (alpha II spectrin) – N terminal fragment AAA51702
2 Human Non-erythroid alpha-spectrin (brain) CAB53710
3 Heat shock 71 kD protein P11142
4 Inter-alpha trypsin inhibitor, heavy chain Q14624
5 Gamma enolase P09104
6 Nedasin S-form (identical to guanine deaminase and AAF13301
KIAA1258)
7 Heat shock 71kD protein P11142
8 Glutamine synthetase P15104
9 IgG gamma chain (leakage from the antibody column) P01857
10 Fructose-biphosphate aldolase C P09972
11 Calmodulin-3 (phosphorylase kinase, delta) NP_005175
12 Ferritin heavy chain P02794
13 Ferritin light chain P02792
14 Ferritin light chain “
15 Flavin reductase P30043
16 Flavin reductase “
17 14kD beta galactoside-binding lectin (galectin) X15256
18 Hemoglobin beta chain P02023
19 Hemoglobin beta chain “
20 Hemoglobin alpha chain P01922
21 Complement C1S component P09871
22 No ID
23 78 kD Glucose regulated protein (IgG binding protein) P11021
24 No ID
25 Glial fibrillary acidic protein NP_002046
26 Vacuolar ATPase isoform VA68 (from hypothalamus) AAF14870
27 No ID
28 Alpha 1-syntrophin U40571
29 IgG kappa chain (leakage from the antibody column) BAA33560
30A 14-3-3 protein zeta/delta (protein kinase C inhibitor P29312
protein)
30B 14-3-3 protein gamma BAA85184
31 No ID
32 Profilin II P35080
33 No ID
34 Neuropolypeptide h3 AAB32876
35 Ferritin heavy chain P02794
8. Page 8
Table 2 represents the proteins from Table 1 which are brain proteins, and are not
ubiquitous or do not represent apparent artifacts from the immunoaffinity
chromatography.
Table 2 – Brain Proteins Bound by Patient Antibody Column
Gel Spot Number Name Accession Number
2 Human Non-erythroid CAB53710
alpha spectrin (brain)
3 Heat shock 71 kD protein P11142
5 Gamma enolase P09104
6 Nedasin –S form (guanine AAF13301
deaminase)
8 Glutamine synthetase P15104
10 Fructose biphosphate P09972
aldolase C
11 Calmodulin-3 NP_005175
(phosphorylase kinase,
delta)
15 Flavin reductase P30043
17 14 kD beta galactoside X15256
binding lectin (galectin)
25 Glial fibrillary acidic NP_002046
protein
26 Vacuolar ATPase isoform AAF14870
VA68 (from hypothalamus)
28 Alpha 1-syntrophin U40571
30 A/B 14-3-3 proteins (protein P29312/BAA85184
kinase C inhibitor proteins)
32 Profilin II P35080
34 Neuropolypeptide h3 AAB32876
Since the sequenced genes in the public protein databases are rapidly being expanded, it
was thought that analysis of proteins containing the conserved epitopes previously found
to exist in strep group A proteins and brain tissue might be fruitful. Since the 5 amino
acid sequence of “KLAKE” was the predominant epitope common to the superantigenic
site of the M5 streptococcal protein, the brain cross-reactive antibodies found in SC
patients, and the myosin heavy chain molecule which was the protein most often
associated with cardiac damage in ARF, this sequence was used for database mining. A
search of the NR database at NCBI revealed a total of 8,934 entries which contained the
keywords “human” and “brain”. A modified BLAST search of the NR database at NCBI
revealed only the following 24 proteins which contained this KLAKE sequence (0.27%
of the estimated human brain proteins present in the database).
9. Page 9
TABLE 3 (Proteins containing KLAKE sequence)
Number Name Accession #
1 Human dynamin 2 P50570
2 Diaphanous 2 isoform 12C NP_009293
3 SWI/SNF related, actin NP_003060
dependent chromatin
regulator
4 Unnamed protein product BAA91778
5 Serine protease 16 NP_005856
6 Homeobox protein ZHX1 NP_009153
7 Non-muscle myosin heavy BAA01989
chain
8 NADH dehydrogenase 1 NP_004535
alpha complex
9 Glycerol kinase CAB54859
10 Moesin (membrane NP_002435
organizing extension spike
protein
11 Cell cycle progression 3 NP_004213
protein
12 Proteasome 26S subunit NP_002807
13 KIAA1258 protein BAA86572
(Nedasin S-form)
14 KIAA1360 protein BAA92598
15 Guanine deaminase NP_004284
(Nedasin S-form)
16 Retinoblastoma binding NP_005047
protein 2
17 RAB-26 protein BAA84707
18 KIAA0820 protein BAA74843
19 Nuclear matrix protein p84 NP_005122
20 Unnamed protein product BAA91331
21 dna-J like HIRA interacting NP_005871
protein
22 KIAA0882 protein BAA74905
23 Mitochondrial import Q15388
receptor subunit
24 RAS-like protein NP_036381
Surprisingly, proteins 13 and 15 from TABLE 3 are homologous to the gene for nedasin
S-form, which is one of the proteins identified in Table 2 which bound to antibodies from
the patient’s serum (Gel Spot #6). Therefore, of only 15 identified brain proteins bound
by the patient’s antibodies, one contained the KLAKE epitope common to streptococcal
M5 protein, cardiac myosin, and a region of the M5 protein which demonstrates
10. Page 10
reactivity with brain cross reacting antibodies observed in Sydenham’s chorea. The
relative tissue expression of the KIAA1258 (Nedasin S-form) gene as measured by
Reverse Transcriptase PCR ELISA is shown in Table 4 (from www.kazusa.or.jp/huge)
TABLE 4 (Expression of KIAA1258/Nedasin S-form gene)
Tissue Relative expression
Heart 1
Brain 1000
Lung 1
Liver 300
Smooth muscle 5
Kidney 1000
Pancreas 3
Spleen 1
Testes 5
Ovary 30
Amygdala 1000
Corpus callosum 80
Cerebellum 1
Caudate nucleus 300
Hippocampus 1000
Substantia nigra 5
Subthalamic nuclei 40
Thalamus 30
Spinal cord 30
Fetal brain 1000
As seen in Table 4, the KIAA1258/nedasin S-form gene is highly expressed in the
caudate nucleus, hippocampus, and amygdala, three areas with previously shown
correlation to OCD, motor function, learning and memory.
Nedasin S-form/Synaptic Associated Proteins (SAPs)
Nedasin S-form is a recently described 51 kD protein which has significant homology to
a superfamily of proteins with deaminase activity.(57) Another group also recently found
a gene with guanine deaminase activity which had an identical predicted amino acid
sequence to nedasin S-form.(58) Guanine deaminase catalyzes the deamination of
guanine, producing xanthine and ammonium. Recent work has suggested that some
deaminase (aminohydrolase) proteins no longer function as enzymes, but use the folds for
other types of biological functions. For example, the C. elegans protein UNC-33 which
belongs to this protein family has been shown to be required for the appropriate direction
of axonal extension of neurons, and mutations in this gene cause severely uncoordinated
movements and abnormalities in neuronal axons.(59) The nedasin gene was shown to
have four alternative splicing isoforms at the C-terminus, and one of these forms (S-form)
11. Page 11
is found primarily in brain and kidney. The expression of nedasin S-form was also found
to increase in parallel with the progress of synaptogenesis in cultured neurons.(57)
Nedasin S-form (but not the other splicing variants) was also found to be co-localized
with NE-dlg/SAP102 protein in neuronal cells. NE (neuroendocrine)-dlg is a member of
an increasingly important family of proteins called MAGUKS (Membrane Associated
Guanylate Kinase homologs). Originally identified as a tumor suppressor gene (discs-
large or dlg) in Drosophila, this family of proteins has been shown to act as essential
scaffolding proteins to organize the structural and functional elements of cell junctions.
In neurons, these dlg proteins are known as synaptic associated proteins (SAPs), and they
play an essential role in clustering and anchoring proteins in the post synaptic membrane
during synaptogenesis.(60) They are also apparently critical for proper signal transmission
and synaptic plasticity in the brain.(61)
NE-dlg is the human homologue of the rat SAP102 protein. (62,63) The SAP proteins have
a number of distinct domains that bind to other proteins including 3 PDZ domains, a src
homology 3 (SH3) region, and a non-enzymatically active guanylate kinase sequence.(64)
The SH3 region apparently acts to bind to cytoskeletal proteins, allowing for anchoring of
the complexes in the membrane. The PDZ domains have been found in many proteins,
and in the case of MAGUKs, they have been shown to mediate binding to the C-terminal
tails of transmembrane proteins including receptors, channels, and cell adhesion
molecules. A number of studies have shown that the rat SAP102 protein is involved in
binding to the C-terminal end of glutamate NMDA type receptors in the post synaptic
density (PSD) of the brain.(63-67) Various other proteins that are involved with
intracellular signaling which are stimulated by glutamate receptor activation including
nitric oxide synthase (NOS) and synaptic Ras-GTPase activating protein (SynGAP) also
interact with the SAP family of proteins.(64,68-70) It is thought that SAPs may not only be
involved in ordering and maintenance of receptor integrity, but may also facilitate
efficient signaling in neurons by keeping enzymes in close proximity.(64) In addition, the
SAP family of proteins interact with subunits from several voltage-dependent K+ (Kv)
channels in neurons, where they are proposed to regulate cell membrane
excitability.(64,71,72) There is also evidence that they interact with inwardly-rectifying K+
channels in neurons.(64)
The NE-dlg/SAP102 protein has been shown to bind to the NR2B type of NMDA
receptors in rat hippocampal neurons, and calmodulin has been shown to be bound also to
the NE-dlg/SAP102 and NMDA receptor complexes.(65,73) One proposed model
speculates that calcium entry for the NMDA receptor can modulate the interaction of NE-
dlg/SAP102 and the NMDA receptors, and the redistribution of these molecules may be
critical in synapse assembly.(65) (see Figure 2 on next page)
The NE-dlg/SAP102 gene has been mapped to the DYT3 (dystonia-parkinsonism
syndrome) region of Xq13.1.(61) It is currently a candidate gene for this neurological
disease, which is characterized by involuntary postural and motor disturbances. These
symptoms appear to be characterized by improper impulse transmission in the basal
ganglia region of the brain.(74)
12. Page 12
Figure 2
Activation of NMDA receptors by glutamate leads to an entry of Ca+2 ions through the
channel. Binding of Ca+2 to calmodulin allows calmodulin to interact with NR1, NE-
dlg/SAP102, and PSD-95. The binding of Ca+2/calmodulin to NR induces detachment of
NMDA receptors from the actin cytoskeleton and their redistribution. The binding of
Ca+2/calmodulin to NE-dlg/SAP102 and PSD-95 results in heteromeric complex
formation of these MAGUK proteins and leads to clustering of the NMDA receptors
during synaptic activity. (from reference 65, figure 9)
13. Page 13
Interestingly, calmodulin was also found to be one of the proteins bound by the patient
antibody column (see Table 1 and 2). Although NMDA receptors are normally found
only in post-synaptic membrane, the NE-dlg/SAP102 protein was also found in one study
to be located in the cytoplasm of neurons where it was not complexed with NMDA
NR2B receptors.(65) The general mechanism proposed for the SAP family of proteins is
one where they assemble receptors and channels in the membrane, and fix them at
specialized domains through their interactions with cell adhesion molecules.
Brain alpha spectrin (fodrin) was also one of the 15 identified brain proteins bound by the
patient antibody coumn (Table 2). This protein is a major component of the post-
synaptic density (PSD), and has been shown to interact with NMDA receptors.(76) It has
been shown to interact selectively with NR1A, NR2A, and NR2B subunits of NMDA
receptors.(76) The spectrin functions to link membrane proteins such as receptors and ion
channels to the actin cytoskeleton, thus anchoring them in place. Three of the 15
identified brain proteins from Table 2 are therefore presumed to be found complexed in
the brain, where they are believed to be critical for synaptic activity.
In the original study by Kuwahara, nedasin S-form was found to interfere with the
association between NE-dlg/SAP102 and NMDA receptor 2B in vitro, suggesting that the
interactions of nedasin S-form may play a role in the clustering of NMDA receptors in
synapses during neuronal development. Due to the assocation of the SAP proteins with
proteins such as NOS and SynGAP, nedasin S-form may also be involved in intracellular
signaling in neurons. In addition, NE-dlg/SAP102 may bind to neuroligin (neural cell
adhesion molecule or NCAM), which is critical for detailing synaptic connections in the
central nervous system.(67,75)
Figure 3 summarizes some of the known and postulated interactions of the NE-
dlg/SAP102 protein.
Nedasin S-form
(blocking action) Figure 3
NE-dlg/SAP102 NMDA NR2B receptors
Nitric Oxide Synthase (NOS)
SynGAP
Voltage Gated K+ channels
Inwardly Rectifying K+ channels
Calmodulin
Neural Cell Adhesion Molecule (NCAM)
ErbB-4 (Tyrosine Kinase receptor)
14. Page 14
Association of NE-dlg/SAP Proteins and Movement Disorders/OCD/ADHD with Areas
of the Brain
As shown in Table 4, the nedasin S-form gene is most highly expressed in the amygdala,
hippocampus, and caudate nucleus in the brain. The glutamate NMDA NR2B gene in
humans has been shown to have a very similar distribution, with the highest levels found
in the fronto-parietal-temporal cortex and hippocampus, and lower levels in the basal
ganglia and amygdala.(77) The gene distributions of both proteins therefore agree with the
proposed association of the nedasin S-form gene and NR2B glutamate receptors.
Other studies lend support to the involvement of these same areas of the brain with
movement disorders, obsessive compulsive disorder (OCD), and attentional difficulties.
The following table summarizes studies which have been done, and the areas of the brain
which have been most frequently found to be atypical or dysfunctional.
Table 5
Disorder Dysfunction/Atypical Imaging method (if Reference
Area of the Brain used)
Tourette’s Basal ganglia (BG) 78
syndrome(TS)/OCD
Huntington’s BG 79
Disease (HD)
Systemic lupus BG MRI 80
erythematosus
(SLE)with chorea
ADHD Caudate MRI 81
ADHD Prefrontal cortex/BG MRI 82
ADHD Prefrontal cortex/BG MRI 83
ADHD Putamen Functional MRI 84
ADHD Prefrontal cortex/BG 85
ADHD Prefrontal MRI 86
cortex/Caudate
TS BG 87
TS Prefrontal cortex/BG 88
SLE with chorea BG MRI 89
TS/OCD BG MRI 90
Movement Disorder BG 91
TS Amygdala 92
OCD BG 93
OCD Caudate 94
TS BG MRI 95
TS BG MRI 96
OCD/tics BG MRI 22
TS/OCD/HD Prefrontal lobes/BG 97
15. Page 15
Disorder Dysfunction/Atypical Imaging Method (if Reference
Area of the Brain used)
Sydenham’s chorea BG MRI 7
(SC)
TS BG MRI 11
SC BG MRI 28
SC BG MRI 98
SC BG MRI 99
SC BG MRI 100
TS/OCD/ADHD Prefrontal lobe/BG 101
OCD Frontal MRI 102
lobe/amygdala
ADHD Frontal lobe PET 103
ADHD Striatum SPECT 104
ADHD Prefrontal lobe SPECT 105
ADHD Right Caudate Functional MRI 106
ADHD Prefrontal MRI 107
lobe/Caudate
ADHD Caudate MRI 108
ADHD Globus pallidus MRI 109
The common thread between the various disorders listed in Table 5 is the involvement of
areas constituting the prefrontal-striatal-thalamo-cortical pathway. These feedback
circuits were first postulated by Alexander et.al. in 1986. They described prefrontal
afferents to basal ganglia relay stations, which would then synapse on thalamic nuclei,
which in turn would feedback to the cortical areas.(110) This circuit would provide
feedback to other cortical regions, and it is currently believed to serve as the substrate for
many of the executive functions in the brain.(111) A simplified schematic of this circuit is
shown in Figure 4.
Signals traveling from the caudate directly to the internal globus pallidus result in
amplification of the thalamic excitatory fibers by disinhibition, which then feedback to
the cortex. This represents the so-called direct pathway. The indirect pathway represents
signals traveling from the caudate to the external globus pallidus, then to the subthalamic
nucleus and internal globus pallidus, and finally reaching the thalamus and then back to
the cortex. Neuronal traffic over the indirect pathway results in inhibition of the system,
and has been described as the brain’s braking mechanism.(112) A deficient inhibitory
activity of the indirect pathway, or excessive stimulation of the direct pathway has been
postulated as a mechanism explaining the pathology of ADHD, Tourette’s syndrome, and
OCD.(89,113-115) Indeed, one study has suggested that most hyperkinetic and hypokinetic
movement disorders are caused by a dysfunctional basal ganglia-thalamo-cortical loop.(91)
The indirect pathway appears to dominate behavior in humans for unknown reasons.(116)
17. Page 17
Hypothesis
Group A streptococcus infections may induce antibodies, in certain susceptible
individuals, which cross react with a protein called nedasin S-form in the brain. It is
postulated that these antibodies precipitate chorea and/or obsessive compulsive
behavioral symptoms by interfering with glutamatergic NMDA NR2B activity in the
cortico-striatal-thalamocortical (CSTC) motor circuits. Dysfunction of nedasin S-form
and NR2B receptors in the CSTC circuits may be involved in the pathogenesis of
disorders such as Tourette syndrome, Sydenham’s chorea, obsessive-compulsive
disorder, autism, and attention deficit hyperactivity disorder (ADHD). Autoantibodies to
nedasin S-form may also interfere with NE-dlg/SAP102 interactions with other proteins
as outlined in Figure 3, and they may represent possible drug targets.
Evidence in Support of Hypothesis
A. Involvement of glutamate and dopamine in movement and neurobehavioral
disorders.
Considerable evidence supports the concept of a reciprocal interaction of glutamate
NMDA receptor activity and dopaminergic activity in the CSTC motor circuits.(118-120) In
one model of chorea, underactivity of the indirect pathway of the CSTC circuits due to
dysfunction of the striatum or subthalamic nuclei results in reduced excitatory (NMDA)
output to the internal globus pallidus, with resultant disinhibition of the thalamus and
excessive motor activity.(121,122)
B. Parkinson’s Disease (PD)
Although perhaps a simplistic comparison, the reduced motor activity observed in PD can
be viewed as a reverse chorea disorder. In PD, the loss of dopaminergic neurons
projecting from the substantia nigra to the striatum results in overactivity of the indirect
pathway, and excessive inhibition of the thalamocortical path, leading to muscle rigidity
and hypokinesia.(123-125) Cognitive declines are also part of the clinical picture in PD.
Parkinsonian brains are characterized by excessive glutamatergic activity in the
projection from the subthalamic nuclei to the internal globus pallidus. (124,126,127) Indeed,
recent animal studies have shown improvements in PD models with agents that block
NMDA NR2B receptors in the brain.(125,128,129) Recent clinical studies in humans have
also shown improvements in PD symptoms with NR2B antagonists.(130-132)
C. Tourette Syndrome (TS)
Tourette syndrome is a lifelong disorder which is characterized by motor and phonic tics
and obsessive compulsive behaviors. It is thought that the cortical excitations are caused
by dopamine excess leading to a reduced inhibition in the indirect CSTC motor
pathway.(87,133,134) Abnormal dopamine uptake sites have been demonstrated in the
caudate and putamen in post mortem studies of TS patients.(135) Dopaminergic
antagonists such as haloperidol are effective in suppressing the tics in many cases,
18. Page 18
although side effects of the drugs limit their use. Dopamine agonists can also precipitate
or exacerbate tics.(9,136) As previously mentioned, TS patients have demonstrated
autoantibodies to the basal ganglia area, and injection of these antibodies into mice
precipitated typical TS symptoms. If these antibodies had the effect of reducing
glutamatergic function in the basal ganglia and amygdala, this could lead to the
dopaminergic sensitivity observed in this disorder. In another post mortem study,
decreased glutamate concentrations were found in the globus pallidus and substantia
nigra pars reticulata of TS patients.(137) In a transgenic mouse model of comorbid TS and
OCD, MK-801 (a non-competitive NMDA antagonist) exacerbated the TS symptoms.(138)
Again, a reciprocal action between glutamatergic and dopaminergic activity is apparent.
D. Sydenham’s chorea (SC)
In SC, where antibodies to the basal ganglia are also observed, there appears to be a
lifelong hypersensitivity to dopaminergic drugs,(139) and an increased severity of the OCD
symptoms with relapse.(140) Although the disease is considered to be self limiting, there
appear to be psychiatric problems such as difficulty in social adjustment that persist long
after the chorea has resolved.(141-143) Clinically, there is substantial overlap in symptoms
between TS, SC, and OCD.(7,8) Palumbo et.al. have coined the term developmental basal
ganglia syndrome (DBGS) to refer to patients with dysfunctional basal ganglia who
present with tics and OCD.(144) Dopaminergic antagonists are also helpful in suppressing
chorea in SC patients.(122) It is interesting that speech impairment also occurs in
approximately 40% of SC cases.(122) Also, one report described an unidentified 45 kD
protein in brain which reacted with serum from SC patients.(145)
E. Autism
Autism is also a lifelong disorder, and includes symptoms of impaired social interactions
and speech, obsessive compulsive symptoms, sensory dysfunctions, and stereotypical
movements. Carlsson has proposed that autism may represent a hypoglutamatergic
disorder.(146) Some evidence for this includes the observation that autistic-like symptoms
can be produced in neurotypical individuals by glutamate antagonists like phencyclidine
(PCP) or ketamine. Serotonin 5-HT2A agonists such as LSD and psilocybin also mimic
many of the perceptual disturbances of autism when given to neurologically normal
individuals. The NMDA receptor antagonism has been shown to lead to enhanced 5-
HT2A receptor transmission, and 5-HT2A stimulation leads to a weaker glutamatergic
transmission. PET brain studies in healthy volunteers show that ketamine and psilocybin
both produce hypermetabolism in the frontal cortex.(147) Direct treatment with glutamate
agonists is hazardous due to the possibility of neurotoxicity and seizures. Animal
experiments by this group have shown that a 5-HT2A receptor antagonist (M100907) is
effective in reducing hyperactivity in mouse psychosis models produced either by
NMDA receptor antagonism or dopamine agonists.(148) They suggest that 5-HT2A
receptor antagonists could be useful in hypoglutamatergic disorders such as autism and
schizophrenia.
19. Page 19
Additional evidence points to hypoglutamatergic conditions producing the symptoms
observed in autism. Mohn et.al. have produced mice which display only 5% of the
normal levels of the essential NR1 glutamate NMDA subunit.(149) These mice did not
sleep with their litter mates, engaged in less social interactions with other mice, and had
reduced sexual activity. Surprisingly, all of these symptoms could be ameliorated with
clozapine (a dopamine antagonist). This again supports the reciprocity of glutamate and
dopamine interactions in behavior. Clozapine has demonstrated some promising results
in autism, although since it also has some 5-HT2A receptor blocking properties, it is
difficult to pinpoint the mechanism.(150) Other evidence points to excess dopaminergic
activity in autism. In animals, autistic behaviors can be induced with dopamine
agonists,(151) and dopamine antagonists such as haloperidol have shown some benefits in
patients.(152-154)
It has long been noted (mostly anecdotally) that autistic patients show improvement
during episodes of fever. In fact, the author’s daughter suddenly spoke using multiple
words for the first time during a bout of influenza when she had a fever. A published
reference to this observation has been made.(155) A possible mechanism for this could be
an enhancement in glutamatergic activity. It has been shown that hyperthermia elevates
the glutamate content in the brain.(156,157) Hypothermia has been shown to reduce the
NMDA receptor mediated excitotoxicity of neurons after ischemic episodes in the brain,
and has even been used therapeutically to limit the extent of ischemic damage after a
stroke.(158,159)
That autism could be due to an abnormal immune system fits with a large body of data.
Studies have reported deficient complement C4B genes,(160,161) altered cytokines,(162) T-
cell changes,(163-166) and other immune system defects.(167,168) An overactive immune
system could lead to a greater tendency toward autoimmune reaction to brain tissue.
Autoantibodies to the nedasin S-form could cause alterations in any of the proteins which
the NE-dlg/SAP102 protein has been shown to bind, including neural cell adhesion
molecule (NCAM). One report has described that autistics showed only 50% of the
normal serum levels of NCAM.(169) NCAM appears to regulate the detachment of
synaptic connections critical in the brain. It is also possible that maternal antibodies to
group A strep, cross reacting with nedasin S-form, could interfere in utero with the
development of the post synaptic density of key areas of the brain, causing autism.
F. Huntington’s disease (HD)
Huntington’s disease is an inherited neurodegenerative disease characterized by chorea
and progressive cognitive decline. It is one of a number of diseases caused by expanded
CAG polyglutamine repeats in the causative gene. Husby et.al. first described that
antibodies to caudate and subthalamic nuclei were observed in 50% of HD patients.(170)
These antibodies could possibly be produced as a response to the glutamatergic
neurotoxicity in these areas. HD is frequently found comorbid with obsessive
compulsive disorder(171) and TS.(94) The basal ganglia and frontal lobes have been found
to be dysfunctional in this disorder.(78,79,94,172) Lower levels of NMDA NR2B expression
in the neostriatum of HD patients have been reported.(173) Dentatorubro-pallidoluysian
20. Page 20
atrophy (DRPLA) is another inherited polyglutamine CAG repeat disease which can
produce a similar clinical presentation to HD.(79)
G. Attention Deficit Hyperactivity Disorder (ADHD)
As previously mentioned, a recent report demonstrated an association between group A
streptococcal infections and ADHD.(28) Higher strep antibody titers predicted MRI
documented changes in the size of the basal ganglia in these patients. Numerous imaging
studies have shown changes in the structures involved in the CSTC circuits of the brain.
Dopaminergic overactivity has been documented in ADHD,(111) and abnormalities in the
D4 dopamine receptor subtype reported.(174) D4 dopamine receptors are abundant in the
globus pallidus, and in GABAergic interneurons in prefrontal cortex.(175)
Castellanos has reported a proposed model for ADHD which describes a mechanism for
the efficacy of stimulants such as methylphenidate in ADHD.(111) In this model,
dopamine neurons in the VTA diffusely innervate the frontal cortex forming the
mesocortical dopamine system, which has few inhibitory autoreceptors. These terminals
regulate cortical inputs. In this circuit, stimulants are hypothesized to increase post
synaptic dopaminergic effects, and integrate inputs from other cortical regions, improving
executive function. Due to the lack of autoreceptors, tolerance in this system is not
produced. However, symptoms of hyperactivity in ADHD are hypothesized to be
associated with overactivity in dopamine circuits which go from the substantia nigra to
the striatum. This circuit is tightly regulated by autoreceptors and feedback from the
cortex, and slow diffusion of stimulants are hypothesized to produce net reduction in
dopaminergic transmission, with the resulting disinhibition of the thalamocortical
pathway and increased motor activity. Since the indirect pathway of the CSTC circuit
has been described as the brain’s braking mechanism, a familiarity with ADHD patients
will lead immediately to the conclusion that you are dealing with a person who “cannot
put on the brakes.”
H. Systemic Lupus Erythematosus (SLE) with CNS involvement
SLE is an autoimmune disease which is characterized by autoantibody formation and
multiple clinical manifestations, including nephritis. Central nervous system
involvement occurs in 35-75% of patients.(176) Up to 4% of SLE patients experience
chorea.(177,178) MRI imaging studies have shown transient alterations in the basal ganglia
of the brain of patients with chorea.(80,89) The transient nature of the imaging
abnormalities has led to speculation about the role of brain autoantibodies to the basal
ganglia as a factor in the chorea. Numerous studies have shown autoantibodies to brain
proteins in patients with SLE and CNS involvement. One study showed that 95% of
patients with SLE/CNS had antibodies to a 50kD protein in synaptic membranes.(179) The
antibodies were also detected in the CSF of these patients. The protein target of these
antibodies was not identified. In a mouse model of SLE with neurobehavioral
disturbances (MRL/lpr mouse), the behavioral disturbances are associated with
autoantibodies.(180) The source of these antibodies is not clear, but there was evidence for
21. Page 21
both passage of antibodies across the blood brain barrier, and intrathecal synthesis of the
antibodies. B cells were found in the brains of MRL/lpr mice, suggesting that some of
the antibodies were produced in the CNS.(181)
The concept of the brain as an immunologically privileged organ has been modified in
recent times.(182-184) Antibodies from serum could enter the brain through areas which
lack a blood brain barrier such as the pineal gland. Alternatively, a number of studies
have shown that peripherally activated B cells can migrate into the CNS, then
differentiate into plasma cells under the influence of cytokines, and begin secreting
antibodies.(183,185,186) Autoantibodies to brain proteins have been shown to be important
in other neurological disorders such as Rasmussen’s encephalitis(182) (glutamate receptor
GluR3), Stiff man syndrome(184) (glutamic acid decarboxylase), and myasthenia
gravis(187) (acetylcholine receptors).
Glutamate NR2B Enhancement
An interesting study was recently reported by Tang et.al.(188) In contrast to the study of
Mohn(149) which showed that mice with reduced expression of glutamate NR1 subunits
showed autistic or schizophrenic behaviors, Tang and his group engineered transgenic
mice which overexpressed the NR2B receptor subunit in cortex, striatum, amygdala, and
hippocampus. These mice showed enhanced activation of NMDA receptors, facilitating
synaptic potentiation. The mice also showed superior learning and memory on a wide
variety of behavioral tasks, demonstrating that NR2B is essential in synaptic plasticity
and memory formation.
Acute Post-Streptococcal Glomerulonephritis (APSGN)
Most cases of acute glomerulonephritis today are associated with group A streptococcal
infections, and occur mostly in children.(189) The nephritogenicity appears to be related to
the specific M serotype of S. pyogenes. The pathogenesis of APSGN is unknown, but it
is thought to be related to an immunological phenomenon involving immune
complexes.(53,190) Although a number of studies have demonstrated antibodies against
kidney protein targets, a consensus target has not been found. Streptokinase, which is
involved in the spread of streptococci through tissue, has been the focus of a number of
studies, although it is thought that additional factors are required for development of the
disease.(53,190) As seen in Table 4, the expression of nedasin S-form is very high in
kidney. It is tempting to speculate that antibodies with the same specificity could be
involved in APSGN, as well as producing heart damage through reaction with myosin,
and chorea/tics by binding nedasin S-form in the brain.
Nedasin S-form - Guanine Deaminase activity
Another possible mechanism for antibodies to nedasin S-form to interfere in brain motor
function and behavior is by a direct inhibitory effect on the guanine deaminase activity of
the protein. Purine nucleotides, nucleosides, and free bases are known to play critical
roles in brain cells. They have been shown to mediate a diverse array of functions
22. Page 22
including neurotransmission, and also longer term effects on cell metabolism, structure,
and function.(191) They can interact at the level of signal-transduction pathways with
neurotransmitters like glutamate. A delicate balance exists between adenine and guanine
nucleotides and free bases in the brain. Interference with the degradative pathway of
guanine could lead to a disturbance in the balance between the nucleotides.
Some evidence exists for altered purine metabolism in a number of CNS disorders. A
critical enzyme for maintenance of nucleoside concentrations in the brain is
hypoxanthine-guanine phosphoribosyl transferase (HGPRT). This enzyme converts
guanine or hypoxanthine back into the nucleoside forms, representing the so-called
“salvage” pathway needed to maintain nucleoside concentrations. A genetic deficiency
in this enzyme produces Lesch-Nyhan syndrome, which is characterized by severe motor
disabilities, cognitive deficits, and disturbances of behavioral control.(192) It is thought to
be attributable to dysfunction in the basal ganglia. Transgenic mice lacking the HGPRT
gene show abnormalities in uptake of guanine and hypoxanthine into cells, increased
rates of purine synthesis, and alterations in nucleotide concentrations.(193)
There is a considerable amount of biochemical data supporting a link between the purines
and the dopaminergic system.(194) Adenosine A2A receptors are highly localized in the
basal ganglia, and have a reciprocal relationship with dopaminergic activity.(194) This has
led to the hypothesis that adenosine receptors may play a role in Huntington’s chorea and
Parkinson’s disease (PD), via interference with the indirect pathway of the cortico-
striatal-thalamocortical circuit.(194) In fact, adenosine A2A antagonists are being
investigated as potential treatments for PD.(195)
Autism has long been known to be associated with dysfunctions in purine metabolism in
a subset of patients.(196-199) Indeed, the term “purine autism” has been used for this group
of patients. Approximately 20-30% of autistic patients have increased uric acid
excretion, resulting from the degradative breakdown of purines. In a recent study,
accelerated rates of purine synthesis were observed, and the ratio of adenine to guanine
nucleotides was found to be lower in this subset of patients.(200) This altered purine
metabolism could also lead to effects on the dopaminergic systems of the basal ganglia.
SUMMARY
Serum was collected from a patient who demonstrated an abrupt onset of motor tics,
coincident with exposure to group A streptococcus. Antibodies from this serum were
found to bind to a protein (nedasin S-form) from human brain which interacts with the
SAP family of proteins involved in regulation of glutamate NMDA activity in the brain.
The pattern of expression of the nedasin gene matches areas of the brain known to be
involved in motor disturbances and obsessive compulsive symptoms. Nedasin S-form
contains an amino acid epitope (KLAKE) common to myosin heavy chain, streptococcal
M5 protein, and a region from the M5 protein which has shown cross reactivity with
antibodies to human basal ganglia.
23. Page 23
It is proposed that antibodies to the nedasin S-form protein, by some mechanism, create a
deficiency in activity of the NMDA NR2B receptors of the cortico-striatal-thalamo-
cortical pathway, leading to the observed motor dysfunction. It is further proposed that
deficient NR2B activity in the brain could represent a pathogenic mechanism in Tourette
syndrome, autism, and attention deficit hyperactivity disorder. Therapies aimed at
correcting this deficient glutamatergic activity may have therapeutic value in all of these
clinical conditions. Finally, it is speculated that an additional or alternative pathogenic
mechanism could be direct interference by the autoantibodies with the guanine deaminase
enzymatic activity of nedasin S-form, leading to disruption of the balance between
purines, and resulting dysfunction in the basal ganglia.
Ongoing and Proposed Studies
Antibodies have been produced in rabbits to three synthetic peptides corresponding to
immunogenic regions of the nedasin S-form protein. Immunaffinity columns are being
prepared in order to isolate the nedasin S-form protein from human brain extracts.
(Note 2011 – these antibodies did not succeed in pulling the
protein out of a brain extract. Indeed, they did not react
with the native protein, probably due to conformational
issues, an unfortunately common problem I had found).
An ELISA technique will be developed to test for the incidence of autoantibodies to this
protein in movement disorders, autism, and ADHD. NE-dlg/SAP102 protein will also be
isolated (or obtained from another source) to study the in vitro interactions of these
proteins with NMDA NR2B receptors.
(Note 2011 – I did develop an ELISA comparing results of
reactivity of my daughters serum with normal sera using the
3 synthetic nedasin peptides as antigen. No difference in
reactivity was seen - possibly due to the conformational
differences with the native protein again).
An appropriate animal model will be developed which can be used to confirm the
hypothesis that the autoantibodies to nedasin S-form can precipitate motor dysfunctions
and/or obsessive compulsive symptoms. The possibility of generating mice with reduced
(not complete knockout) NMDA NR2B gene expression in the brain will be explored,
since knockout mice without NR2B subunits apparently do not survive. In vitro studies
will also be performed to investigate the possibility of an altered balance between purines
in an appropriate model system.
(This work was not attempted – May, 2011)
24. Page 24
(Note 2011 - The result of this project pointed toward a protein (nedasin or
guanine deaminase) which blocks the action of some other proteins involved in synaptic
connections and scaffolding.
After this report was written, futher studies were done to examine the reactivity of
antibodies to streptococcal M5 protein with various tissues. Polyclonal antibodies were
prepared in rabbits to the streptococcal M5 protein and immunohistochemical studies
performed using various human tissues. Unfortunately, the antibodies showed broad
reactivity to most peripheral tissues as well as to brain tissue. Due to this lack of
specificity, the research was discontinued.
However, recent research has found an association between neuroligin and neurexin
defects and autism. The fact that these are also NMDA glutamate receptor proteins may
be of interest in this regard
.
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