Neurological Proteins in Autism

Specific proteins

It must be remembered that some proteins have been taken from brain post mortem samples and which may be present for some other reason apart from the autism itself.

 

Proteins that are discussed in autism:

  • Neuropeptides e.g. VIP, neuropeptide Y, encephalins, secretin. Now, about 100 different peptides are known to be released by different populations of neurons in the mammalian brain. Metabolic or G-protein-coupled receptors expressed by selective populations of neurons. In essence they act as specific signals between one population of neurons and another.  Peptides have much more diverse effect than transmitters; amongst other things, they can affect gene expression. They are held in large dense-core vesicles, often found in all parts of a neuron, including the soma, dendrites, axonal swellings and nerve endings, whereas the small synaptic vesicles are mainly found in clusters at presynaptic locations.
  • Neurotrophins .  e.g. Brain-derived neurotrophic factor, neurotrophin-4, a family of proteins, which induce the survival of neurons.  They belong to a class of growth factors, secreted proteins, which are capable of signaling to particular cells to survive, differentiate, or grow…and they have involvement with immunity (see Vega).
  • Reelin.  This regulates telencephalitic and cerebellar lamination during mammalian development of rats.  It is present, however in all mammals and its action in them is not quite so clear.   The finding that in some cases in animal models the modification of the reelin gene will create brain activity changes. In humans they can show some genetic changes but in other cases it is a decrease in the expression of the gene, which itself may well be normal.
  • Phosphodiesterase 4.  The cyclic adenosine monophosphate-specific phosphodiesterase-4 (PDE4) gene family is the target of several potential therapeutic inhibitors and the PDE4B gene has been associated with schizophrenia and depression.
  • Aquaporin and Connexin 43.  These are peptides that are found to interact with neurones but are derived from glia. 
  • Glial fibrillary acid protein.  Glial fibrillary acidic protein (GFAP) is an intermediate filament protein expressed predominantly in astrocytes.
  • Glutamic acid decarboxylase.  Glutamic acid is a neurotransmitter that is present in the brain and, following its stimulation of a dendrite it is destroyed by the decarboxylase.  This report of a decrease in the enzyme suggests that there may be an increase in the glutamate, which may have effects on brain activity.
  • APO-E.  No association was found between the expression of Apolipoprotein E and autism, as opposed to several other brain conditions (CJD etc).
  • Secretin.   This is a hormone produced and used in the gut that is also found as a neuropeptide in the brain.
  • Serotonin transporter: see histopathology and serotonin

 

Others?

It is clear that there are many other genes and proteins that have not been investigated. See: Lam KS, Aman MG, Arnold LE. Neurochemical correlates of autistic disorder: a review of the literature. Res Dev Disabil. 2006 May-Jun;27(3):254-89. Epub 2005 Jul 5. a review. (Review of neurochemical investigations in autistic disorder revealed that a wide array of transmitter systems have been studied, including serotonin, dopamine, norepinephrine, acetylcholine, oxytocin, endogenous opioids, cortisol, glutamate, and gamma-aminobutyric acid (GABA).

 

 

 

This shows how neurotrophins are released by dendrites and glia (like astrocytes) and are taken to the nucleus of the target neurone, which then makes the protein (small purple lines), which acts as a receptor for more of the neurotrophin

 

 

Neuropepetides and Neurotrophins in Autism

The complex nature of neuropeptides means that it is exceptionally difficult to be sure of their action in the normal brain.  They modify the reaction of neurones to classical transmitter compounds, which act to cause the electrical change in the cellular surface.  There are claims that some are produced as result of genetic changes.

 

Nelson KB, Grether JK, Croen LA, Dambrosia JM, Dickens BF, Jelliffe LL, Hansen RL, Phillips TM. Neuropeptides and neurotrophins in neonatal blood of children with autism or mental retardation. Ann Neurol. 2001 May;49(5):597-606. (Several neurotrophins –NTs- with potent immunomodulatory actions, including neuropeptide Y, substance P, calcitoningene-related peptide (CGRP), vasoactive intestinal peptide(VIP), BDNF, and NT-4/5, which have multiple affects on neurodevelopment and neuron maintenance, have been implicated in ASD. Analysis of neonatal blood spots by recyclingimmunoaffinity chromatography found that BDNF, VIP, CGRP,and NT-4/5 were elevated in ASD compared with typically developing control children but could not be distinguished from those with mental retardation).  Note that these may actually have something to do with the immune changes that are seen see: Vega JA, García-Suárez O, Hannestad J, Pérez-Pérez M, Germanà A. Neurotrophins and the immune system. J Anat. 2003 Jul;203(1):1-19.

 

Miyazaki K, Narita N, Sakuta R, Miyahara T, Naruse H, Okado N, Narita M. Serum neurotrophin concentrations in autism and mental retardation: a pilot study.  Brain Dev. 2004 Aug;26(5):292-5.  (serum levels of the brain-derived neurotrophic factor and neurotrophin-4 (NT-4) in the patients diagnosed with autism (n=18) and mental retardation (n=20), or healthy controls (n=16), using enzyme-linked immunosorbent assay. There tended to be a higher concentration of serum BDNF found in the autistic group ( P <0.05 by analysis of variance (ANOVA)) and the mental retardation group ( P <0.001 by ANOVA). )

 

Young LJ, Pitkow LJ, Ferguson JN. Neuropeptides and social behaviour: animal models relevant to autism. Mol Psychiatry. 2002;7 Suppl 2:S38-9. (explains how the neuropeptide oxytocin results in voles’ receptor protein and this may explain some of the symptoms seen in autism)

 

Chen X, Liu H, Shim AH, Focia PJ, He X. Structural basis for synaptic adhesion mediated by neuroligin-neurexin interactions. Nat Struct Mol Biol. 2008 Jan;15(1):50-6. Epub 2007 Dec 16.

 

Vega JA, García-Suárez O, Hannestad J, Pérez-Pérez M, Germanà A. Neurotrophins and the immune system. J Anat. 2003 Jul;203(1):1-19. (this is a major review of the interaction between the peptides that are found in the brain to have interactive effects and the findings that they also interact with the immune system.  At this point there is almost certainly more information to be found but this is a useful reference article)

 

 

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Aquaporin and Connexin 43

 

Fatemi SH, Folsom TD, Reutiman TJ, Lee S. Expression of astrocytic markers aquaporin 4 and connexin 43 is altered in brains of subjects with autism. Synapse. 2008 Jul;62(7):501-7. (studies have provided evidence of neuroglial responses and neuroinflammation in autism. Postmortem brain tissues from Brodmann's Area 40 (BA40, parietal cortex), Brodmann's Area 9 (BA9, superior frontal cortex), and cerebella of subjects with autism and matched controls were subject to SDS-PAGE and western blotting. Connexin 43 expression was increased significantly in BA9. Aquaporin 4 expression was decreased significantly in cerebellum. These data suggest that changes are apparent in markers for abnormal glial-neuronal communication (connexin 43 and aquaporin 4) in brains of subjects with autism.

 

Phosphodiesterase 4

Braun NN, Reutiman TJ, Lee S, Folsom TD, Fatemi SH. Expression of phosphodiesterase 4 is altered in the brains of subjects with autism. Neuroreport. 2007 Nov 19;18(17):1841-4.  (they look for various phosphodiesterase forms exposed in areas of the brain of autistic children and compare them with controls.  The problem with this study is that they have looked for many different proteins and so they were very likely to find ones that were altered in autism)

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Reelin

A protein of unknown value in humans that is found modified in some rats with a psychological modification.  Responsible for correct lamination of the brain during the embryonic period and cell signaling and synaptic plasticity in the adult life.

 

Fatemi SH, Snow AV, Stary JM, Araghi-Niknam M, Reutiman TJ, Lee S, Brooks AI, Pearce DA. Reelin signaling is impaired in autism. Biol Psychiatry. 2005 Apr 1;57(7):777-87.  (To further investigate these studies, brain levels of Reelin protein and mRNA and mRNAs for VLDLR, Dab-1, and GSK3 were investigated. METHODS: Postmortem superior frontal, parietal, and cerebellar cortices of age, gender, and postmortem interval-matched autistic and control subjects were subjected to SDS-PAGE and Western blotting of Reelin protein. Quantitative reverse transcriptase polymerase chain reaction analysis of Reelin, VLDL-R, Dab-1, and GSK3 mRNA species in superior frontal and cerebellar cortices of autistic and control subjects were also performed. RESULTS: Reelin 410, 330, and 180 kDa/beta-actin values were reduced significantly in frontal and cerebellar, and nonsignificantly in parietal, areas of autistic brains versus control subjects, respectively. The mRNAs for Reln and Dab-1 were reduced significantly whereas the mRNA for Reln receptor VLDLR was elevated significantly in superior frontal and cerebellar areas of autistic brains versus control brains, respectively. CONCLUSIONS: Reductions in Reelin protein and mRNA and Dab 1 mRNA and elevations in Reln receptor VLDLR mRNA demonstrate impairments in the Reelin signalling system in autism)

 

Bonora E, Beyer KS, Lamb JA, Parr JR, Klauck SM, Benner A, Paolucci M, Abbott A, Ragoussis I, Poustka A, Bailey AJ, Monaco AP; International Molecular Genetic Study of Autism (IMGSAC). Analysis of reelin as a candidate gene for autism. Mol Psychiatry. 2003 Oct;8(10):885-92.

 

Devlin B, Bennett P, Dawson G, Figlewicz DA, Grigorenko EL, McMahon W, Minshew N, Pauls D, Smith M, Spence MA, Rodier PM, Stodgell C, Schellenberg GD; CPEA Genetics Network. Alleles of a reelin CGG repeat do not convey liability to autism in a sample from the CPEA network. Am J Med Genet B Neuropsychiatr Genet. 2004 Apr 1;126(1):46-50.

 

Serajee FJ, Zhong H, Mahbubul Huq AH. Association of Reelin gene polymorphisms with autism. Genomics. 2006 Jan;87(1):75-83. Epub 2005 Nov 28.

 

Skaar DA, Shao Y, Haines JL, Stenger JE, Jaworski J, Martin ER, DeLong GR, Moore JH, McCauley JL, Sutcliffe JS, Ashley-Koch AE, Cuccaro ML, Folstein SE, Gilbert JR, Pericak-Vance MA. Analysis of the RELN gene as a genetic risk factor for autism. Mol Psychiatry. 2005 Jun;10(6):563-71.

 

Fatemi SH. Reelin glycoprotein in autism and schizophrenia. Int Rev Neurobiol. 2005;71:179-87. Review.

 

Fatemi SH. The role of Reelin in pathology of autism. Mol Psychiatry. 2002;7(9):919-20. Review.  (notably changes are seen in some cases genetically, and in some cases when investigated post mortem.  The article puts over the idea of Reelin as being a major genetic cause but this is not well demonstrated.  It is an editorial review of Zhang’s article below).

 

Zhang H, Liu X, Zhang C, Mundo E, Macciardi F, Grayson DR, Guidotti AR, Holden JJ. Reelin gene alleles and susceptibility to autism spectrum disorders. Mol Psychiatry. 2002;7(9):1012-7.

 

Dutta S, Guhathakurta S, Sinha S, Chatterjee A, Ahmed S, Ghosh S, Gangopadhyay PK, Singh M, Usha R. Reelin gene polymorphisms in the Indian population: a possible paternal 5'UTR-CGG-repeat-allele effect on autism. Am J Med Genet B Neuropsychiatr Genet. 2007 Jan 5;144(1):106-12

 

Ashley-Koch AE, Jaworski J, Ma de Q, Mei H, Ritchie MD, Skaar DA, Robert Delong G, Worley G, Abramson RK, Wright HH, Cuccaro ML, Gilbert JR, Martin ER, Pericak-Vance MA. Investigation of potential gene-gene interactions between APOE and RELN contributing to autism risk. Psychiatr Genet. 2007 Aug;17(4):221-6. (Thus, we conclude that there is no main effect of APOE in our autism data set, nor is there any evidence for a joint effect of APOE with RELN. RELN, however, remains a good candidate for autism susceptibility)

 

Fatemi SH, Stary JM, Egan EA. Reduced blood levels of reelin as a vulnerability factor in pathophysiology of autistic disorder. Cell Mol Neurobiol. 2002 Apr;22(2):139-52.

 

Fatemi SH. Reelin glycoprotein: structure, biology and roles in health and disease. Mol Psychiatry. 2005 Mar;10(3):251-7.

 

Glial fibrillary acid protein

(NB see autoantibodies for GFAP and its presence in CSF)

 

Laurence JA, Fatemi SH. Glial fibrillary acidic protein is elevated in superior frontal, parietal and cerebellar cortices of autistic subjects. Cerebellum. 2005;4(3):206-10. (‘Immune system dysregulation has been hypothesized to be involved in this disorder. We quantified levels of glial fibrillary acidic protein (GFAP) and ss-actin in three areas of the brain, namely, area 9, area 40 and cerebellum, in age matched autistic and control postmortem specimen using SDS-PAGE and western blotting techniques. Significant elevations in levels of GFAP were observed in all three brain areas in autism. This report confirms a recent report showing microglial and astroglial activation in autism’)

 

Fatemi SH, Araghi-Niknam M, Laurence JA, Stary JM, Sidwell RW, Lee S. Glial fibrillary acidic protein and glutamic acid decarboxylase 65 and 67 kDa proteins are increased in brains of neonatal BALB/c mice following viral infection in utero. Schizophr Res. 2004 Jul 1;69(1):121-3.

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Glutamic Acid Decarboxylase

 

Fatemi SH, Halt AR, Stary JM, Kanodia R, Schulz SC, Realmuto GR. Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices. Biol Psychiatry. 2002 Oct 15;52(8):805-10. (‘We observed a lower expression of PDE4A5, PDE4B1, PDE4B3, PDE4B4, and PDE4B2 in the cerebella of subjects with autism when compared with matched controls. In BA9, we observed the opposite: a higher expression of PDE4AX, PDE4A1, and PDE4B2 in subjects with autism. No changes were observed in BA40. Our results demonstrate altered expressions of the PDE4A and PDE4B proteins’)

 

Fatemi SH. The hyperglutamatergic hypothesis of autism.  Prog Neuropsychopharmacol Biol Psychiatry. 2008 Apr 1;32(3):911, author reply 912-3. Epub 2007 Nov 13

 

ApoProtein-E (a protein found on the surface of cells)

 

Raiford KL, Shao Y, Allen IC, Martin ER, Menold MM, Wright HH, Abramson RK, Worley G, DeLong GR, Vance JM, Cuccaro ML, Gilbert JR, Pericak-Vance MA. No association between the APOE gene and autism. Am J Med Genet B Neuropsychiatr Genet. 2004 Feb 15;125(1):57-60

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Secretin 

This is generally thought of as a hormone but, like many other hormones it has a direct activity on neuronal tissue, and can commonly penetrate the blood brain barrier.  When secretin was inoculated into autistic children as a potential treatment it was considered that this was to do with gut modification that it would bring about.  However, the consideration that it may be acting directly on the brain came later.

 

Ng SS, Yung WH, Chow BK. Secretin as a neuropeptide. Mol Neurobiol. 2002 Aug;26(1):97-107. (a review of the action of secretin neuropeptide: realising that there is a complex activity of secretin)

 

Banks WA, Goulet M, Rusche JR, Niehoff ML, Boismenu R. Differential transport of a secretin analog across the blood-brain and blood-cerebrospinal fluid barriers of the mouse. J Pharmacol Exp Ther. 2002 Sep;302(3):1062-9. (shows how the drug is passed across into the  brain from the blood system)

 

Toda Y, Mori K, Hashimoto T, Miyazaki M, Nozaki S, Watanabe Y, Kuroda Y, Kagami S. Administration of secretin for autism alters dopamine metabolism in the central nervous system. Brain Dev. 2006 Mar;28(2):99-103.  (a complex study in which they gave 12 autistic children some i.v. secretin and looked for improvements in biopterin, 5HIAA, and homovanillinic acid –taken as signs of irritation, serotonin turnover and dopamine turnover- these were found in 7 but all of those with raised biopterin results initially)

 

Welch MG, Keune JD, Welch-Horan TB, Anwar N, Anwar M, Ludwig RJ, Ruggiero DA. Secretin: hypothalamic distribution and hypothesized neuroregulatory role in autism. Cell Mol Neurobiol. 2004 Apr;24(2):219-41.

 

Nishijima I, Yamagata T, Spencer CM, Weeber EJ, Alekseyenko O, Sweatt JD, Momoi MY, Ito M, Armstrong DL, Nelson DL, Paylor R, Bradley A. Secretin receptor-deficient mice exhibit impaired synaptic plasticity and social behaviour. Hum Mol Genet. 2006 Nov 1;15(21):3241-50.  (this was an interesting finding in that it suggested that the social changes seen in brains that had no secretin receptor in the brain and hence put forward the idea that there was a genetic factor that may cause the autism.  Also it indicated that injected secretin would not be expected to work as a treatment unless it was the gene for secretin production that was affected).

 

Molloy CA, Manning-Courtney P, Swayne S, Bean J, Brown JM, Murray DS, Kinsman AM, Brasington M, Ulrich CD 2nd. Lack of benefit of intravenous synthetic human secretin in the treatment of autism. J Autism Dev Disord. 2002 Dec;32(6):545-51. (this is just one of the studies that found this.  Originally Horvath’s 3 cases to which he gave secretin have been interesting and certainly specific cases claim great improvements but the statistics will not stand up over larger studies)

 

 

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