The IPAK Model of ASD Causality (aka "The IPAK Model")
After reviewing thousands of studies over two years, a more complete picture of the causality of ASD has now emerged.
We are working on an interactive web resource to allow the public and researchers to access the scientific literature in support of each component of this ASD causality model.
Note that this model includes an important component of genetic susceptibility, never addressed in whole-population ecological correlational association studies.
Again, the hypothesis of genetic susceptibility has not been addressed.
USAGE: Please use with citation and reference "Personal Communication, Dr. J. Lyons-Weiler, The Institute for Pure and Applied Knowledge",with a link to this webpage.
Also available for download as .tiff, .ppt
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Research listings:
Vaccine Metals and ER Stress
Aremu DA, Ezomo OF, Meshitsuka S. 2011. Gene expression in primary cultured astrocytes affected by aluminum: alteration of chaperons involved in protein folding. Environ Health Prev Med 16(1):16-24.
Franchi L, Núñez G. 2008. The Nlrp3 inflammasome is critical for aluminium hydroxide-mediated IL-1beta secretion but dispensable for adjuvant activity. Eur J Immunol 38(8):2085-9.
Rizvi SH, Parveen A, Ahmad I, Ahmad I, Verma AK, Arshad M, Mahdi AA. 2016. Aluminum Activates PERK-EIF2α Signaling and Inflammatory Proteins in Human Neuroblastoma SH-SY5Y Cells. Biol Trace Elem Res 172(1):108-19.
Rizvi MSH, Parveen A, Verma AK, Ahmad I, Arshad M, Mahdi AA. 2014. Aluminium induced endoplasmic reticulum stress mediated cell death in SH-SY5Y neuroblastoma cell line is independent of p53. PLoS One 30;9(5):e98409.
Stamogiannos A, Papakyriakou A, Mauvais FX, van Endert P, Stratikos E. 2016. Screening Identifies Thimerosal as a Selective Inhibitor of Endoplasmic Reticulum Aminopeptidase 1. ACS Med Chem Lett 7(7):681-5.
Direct Mitotoxicity
Kahrizi F. 2016. Repeated Administration of Mercury Intensifies Brain Damage in Multiple Sclerosis through Mitochondrial Dysfunction. Iran J Pharm Res 15(4):834-41.
Lemire J1, Mailloux R, Puiseux-Dao S, Appanna VD. 2009. Aluminum-induced defective mitochondrial metabolism perturbs cytoskeletal dynamics in human astrocytoma cells. J. Neurosci Res 87(6):1474-83
Sharpe, MA et al. 2012. Thimerosal-Derived Ethylmercury Is a Mitochondrial Toxin in Human Astrocytes: Possible Role of Fenton Chemistry in the Oxidation and Breakage of mtDNA. J Toxicol 2012:373678.
Vaccine ER Stress + Unfolded Protein ER Stress = ER Hyperstress
Lyons-Weiler J. 2018. Autism is an Acquired Cellular Detoxification Deficiency Syndrome with Hetergeneous Genetic Predisposition. Autism 8(1):224.
ER Hyperstress -> Impaired Cellular Detoxification
ER/Mito citations in Lyons-Weiler J. 2018. Autism is an Acquired Cellular Detoxification Deficiency Syndrome with Hetergeneous Genetic Predisposition. Autism 8(1):224. See text for Golgi citations.
Berridge MJ. 2002. The endoplasmic reticulum: A multifunctional signaling organelle. Cell Calcium 32(5-6):235-49.
Choi JY, Won NH, Park, JD, Jang S, et al. 2016. From the Cover: Ethylmercury-Induced Oxidative and Endoplasmic Reticulum Stress-Mediated Autophagic Cell Death: Involvement of Autophagosome-Lysosome Fusion Arrest. Toxicol Sci 154(1):27-42.
Crider A, Ahmed AO, Pillai A. 2017. Altered Expression of Endoplasmic Reticulum Stress-Related Genes in the Middle Frontal Cortex of Subjects with Autism Spectrum Disorder. Mol Neuropsychiatry 3(2):85-91.
De Jaco, A. 2006. A mutation linked with autism reveals a common mechanism of endoplasmic reticulum retention for the alpha, beta-hydrolase fold protein family. J Biol Chem 281:9667-76.
Delhey LM, Kilinc EN, Yin L, Slattery JC, et al. 2017. The Effect of Mitochondrial Supplements on Mitochondrial Activity in Children with Autism Spectrum Disorder. J Clin Med 6(2):18.
Foufelle F, Fromenty B. 2016. Role of endoplasmic reticulum stress in drug-induced toxicity. 4(1):e00211.
Fujita E, Dai H, Tanabe Y, Zhiling Y, et al. 2010. Autism spectrum disorder is related to endoplasmic reticulum stress induced by mutations in the synaptic cell adhesion molecule, CADM1. Cell Death Dis 1:e47.
Griffiths KK, Levy RJ. 2017. Evidence of Mitochondrial Dysfunction in Autism: Biochemical Links, Genetic-Based Associations, and Non-Energy-Related Mechanisms. Oxid Med Cell Longev 2017:4314025.
Haddur E, Ozkaya AB, Ak H, Aydin HH. 2015. The effect of calcitriol on endoplasmic reticulum stress response. Biochem Cell Biol 93(3):268-71.
Iurlaro, R. 2016. Cell death induced by endoplasmic reticulum stress. 283:2640-52.
Kanemoto S, Wang H. 2012. Roles of Endoplasmic Reticulum Stress in Neurodegenerative Diseases. Translational Medicine 2(1):1000e108.
Kawada K. 2016. ER Stress-induced Aberrant Neuronal Maturation and Neurodevelopmental Disorders. Yakugaku Zasshi 136(6):811-15.
Kozlov, AV, Duvigneau, JC., Miller, I, Nürnberger, S, et al. 2009. Endotoxin causes functional endoplasmic reticulum failure, possibly mediated by mitochondria. Biochim Biophys Acta 1792(6):521-30.
Leclerc D, Rozen R. 2008. Endoplasmic reticulum stress increases the expression of methylenetetrahydrofolate reductase through the IRE1 transducer. J Biol Chem 283:3151-60.
Lemire J, Mailloux R, Puiseux DS, Appanna VD. 2009. Aluminum-induced defective mitochondrial metabolism perturbs cytoskeletal dynamics in human astrocytoma cells. J Neurosci Res 87(6): 1474-83.
Malhotra JD, Kaufman, RJ. 2011. ER stress and its functional link to mitochondria: Role in cell survival and death. Cold Spring Harb Perspect Biol 3(9):a004424.
Momoi T. 2009. Genetic factors and epigenetic factors for autism: endoplasmic reticulum stress and impaired synaptic function. Cell Biol Int 34:13-19.
Mustafa Rizvi SH, Parveen A, Verma AK, Ahmad I, Arshad M, et al. 2014. Aluminium induced endoplasmic reticulum stress mediated cell death in SH-SY5Y neuroblastoma cell line is independent of p53. PLoS One 9(5):e98409.
Palsamy, P, Bidasee, KR, Shinohara, T. 2014. Valproic acid suppresses Nrf2/Keap1 dependent antioxidant protection through induction of endoplasmic reticulum stress and Keap1 promoter DNA demethylation in human lens epithelial cells. Exp Eye Res 121:26-34.
Paschen W, Frandsen A. 2001. Endoplasmic reticulum dysfunction-a common denominator for cell injury in acute and degenerative diseases of the brain? J Neurochem 79(4):719-25.
Riek AE, Oh J, Sprague JE, Timpson A, et al. 2012. Vitamin D suppression of endoplasmic reticulum stress promotes an antiatherogenic monocyte/macrophage phenotype in type 2 diabetic patients. J Biol Chem 287:38482-94.
Roussel BD, Kruppa AJ, Miranda E, Crowther DC, et al. (2013) Endoplasmic reticulum dysfunction in neurological disease. Lancet Neurol 12(1):105-18.
Sano R, Reed JC. 2013. ER stress-induced cell death mechanisms. Biochim Biophys Acta 1833(12):3460-70.
Saveanu L, Carroll O, Lindo V, Del Val M, Lopez D, et al. 2005. Concerted peptide trimming by human ERAP1 and ERAP2 aminopeptidase complexes in the endoplasmic reticulum. Nat Immunol 6:689-67.
Sharpe MA, Livingston AD, Baskin DS. 2012. Thimerosal-Derived Ethylmercury Is a Mitochondrial Toxin in Human Astrocytes: Possible Role of Fenton Chemistry in the Oxidation and Breakage of mtDNA, J Toxicol 2012:373678.
Sprenkle NT, Sims SG, Sánchez CL, Meares GP. 2017. Endoplasmic reticulum stress and inflammation in the central nervous system. Mol Neurodegener 12:42.
Stamogiannos A, Papakyriakou A, Mauvais FX, van Endert P, et al. 2016. Screening Identifies Thimerosal as a Selective Inhibitor of Endoplasmic Reticulum Aminopeptidase 1. ACS Med Chem Lett 7(7):681-85.
Xu D, Su C, Song X, Shi Q, et al. 2015. Polychlorinated biphenyl quinone induces endoplasmic reticulum stress, unfolded protein response, and calcium release. Chem Res Toxicol 28(6):1326-37.
Zhang C, Milunsky JM, Newton S, Ko J, Zhao G, et al. (2009) A neuroligin-4 missense mutation associated with autism impairs neuroligin-4 folding and endoplasmic reticulum export. J Neurosci 29(35): 10843-54.
Leaky Gut -> Absorption of Toxins
De Chambrun GP, Body-Malapel M, Frey-Wagner I, Djouina M, et al. 2014. Aluminum enhances inflammation and decreases mucosal healing in experimental colitis in mice. Mucosal Immunol 7(3):589–601.
Kirschbaum BB, Schoolwerth C. 1989. Acute Aluminum Toxicity Associated with Oral Citrate and Aluminum-Containing Antacids. Amer J Med Sci 297(1):9-11.
Tian F, Yu L, Zhai Q, Xiao Y, et al. 2017. The therapeutic protection of a living and dead Lactobacillus strain against aluminum-induced brain and liver injuries in C57BL/6 mice. PLoS One. 12(4):e0175398.
Yu L, Zhai Q, Tian F, Liu X, et al. 2016. Potential of Lactobacillus plantarum CCFM639 in Protecting against Aluminum Toxicity Mediated by Intestinal Barrier Function and Oxidative Stress. Nutrients 8(12):E783.
Yu, L, Zhia Q, Tian F, Liu X, et al. 2017. Lactobacillus plantarum CCFM639 can prevent aluminium-induced neural injuries and abnormal behaviour in mice. J Functional Foods 30:142-50.
Yu, L., Zhai Q, Zhu J, Zhang, C, et al. 2017. Dietary Lactobacillus plantarum supplementation enhances growth performance and alleviates aluminum toxicity in tilapia. Ecotox Environ Safety 143:307-14.
Chronic Microglial Activation -> Leaky Gut
Grubišić V, Parpura V. 2015. The second brain in autism spectrum disorder: could connexin 43 expressed in enteric glial cells play a role? Front Cell Neurosci. 9:242.
Kirchgessner AL, Liu MT, Alcantara F. 1997. Excitotoxicity in the enteric nervous system. J Neurosci. 17(22):8804-16.
Unfolded Proteins -> Autoimmunity
Clavarino G, Adriouach S, Quesada JL, Clay M, et al. 2016. Unfolded protein response gene GADD34 is overexpressed in rheumatoid arthritis and related to the presence of circulating anti-citrullinated protein antibodies. 49(3):172-8.
Garaud JC, Schickel JN, Blaison G, Knapp AM, et al. 2011. B cell signature during inactive systemic lupus is heterogeneous: toward a biological dissection of lupus. PLoS One 6(8):e23900.
Immunoneuroexcitotoxicity -> Aberrant Pruning
Cunningham CL, Martínez-Cerdeño V, Noctor C, et al. 2013. Microglia regulate the number of neural precursor cells in the developing cerebral cortex. J Neurosci. 33(10):4216-33.
Fiorentino M, Sapone A, Senger S, Camhi SS, et al.. 2016. Blood–brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders. Molecular Autism 7:49
Strunecka A, Blaylock R, Patocka J, Strunecky O, et al. 2018. Immunoexcitotoxicity as the central mechanism of etiopathology and treatment of autism spectrum disorders: A possible role of fluoride and aluminum. Surg Neurol Int 9:74.
Aberrant Pruning -> Altered Development
Kim HJ, Cho MH, Shim WH, Kim JK, et al. 2017. Deficient autophagy in microglia impairs synaptic pruning and causes social behavioral defects. Mol Psychiatry 22(11):1576-84.
Thomas MS, Davis R, Karmiloff-Smith, A, Knowland, VCP, et al. 2016. The over-pruning hypothesis of autism. Dev Sci 19(2):284-305.
Vaccine Metals Release -> Autoimmunity
Tomljenovic L, Shaw CA. 2012. Mechanisms of aluminum adjuvant toxicity and autoimmunity in pediatric populations. Lupus 21(2):223-30.
Autoimmunity -> Altered Development
Braunschweig D, Ashwood P, Krakowiak P, Hertzo-Picciotto R, et al., 2008. Autism: maternally derived antibodies specific for fetal brain proteins. Neurotoxicology 29(2):226-31.
Cabanlit M, Wills S, Goines P, Ashwood P, et al. 2007. Brain-specific autoantibodies in the plasma of subjects with autistic spectrum disorder. Ann N Y Acad Sci. 1107(1):92-103.
Malkki H. 2016. Neurodevelopmental disorders: Maternal antibodies induce autism-like phenotype in mice. Nat Rev Neurol 12:678-9.
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