Protein-Protein Interactions and Novel Biomarkers of Autism
Creators: name: Abdel-Missih, Tony
name: Abdel-Missih, Nataly
name: Silverman, Rosalind
name: Silverman, Lorelei
Publisher: name: figshare
Year: 2020
Subjects: subject: Biomarkers
subject: 110902 Cellular Nervous System
subject: FOS: Clinical medicine
subject: FOS: Clinical medicine
subject: 110903 Central Nervous System
subject: 111502 Clinical Pharmacology and Therapeutics
subject: 111704 Community Child Health
subject: FOS: Health sciences
subject: FOS: Health sciences
subject: Diseases
subject: 110199 Medical Biochemistry and Metabolomics not elsewhere classified
subject: 110101 Medical Biochemistry: Amino Acids and Metabolites
subject: 110106 Medical Biochemistry: Proteins and Peptides (incl. Medical Proteomics)
subject: 110107 Metabolic Medicine
subject: 110904 Neurology and Neuromuscular Diseases
subject: 110999 Neurosciences not elsewhere classified
subject: 110319 Psychiatry (incl. Psychotherapy)

description: Protein-Protein Interactions and Novel Biomarkers for AutismAuthors: Tony Abdel-Missih, Nataly Abdel-MissihSupervisors: Dr. Lorelei Silverman, Dr. Rosalind SilvermanINTRODUCTIONAutism Spectrum Disorder (ASD) is a term used to refer to a heterogeneous set ofneurodevelopmental disorders that can cause significant difficulties with social skills,communication and behavioral issues including restricted and repetitive behaviors, interests oractivities. Although autistic patients do not visually appear any different, the way they interactwith others can differ substantially from neurotypicals. The severity of these deficits varieswidely from mild to debilitating. The “Spectrum” in ASD now encompasses several otherconditions that were previously classified individually including Autistic Disorder and AspergerSyndrome.EPIDEMIOLOGYASD is a very common disorder affecting people all over the world. According to the worldhealth organization (WHO), ASD is estimated to affect 1 in 160 children. Although prevalencereported may vary significantly across studies, many have reported figures that are substantiallyhigher. Furthermore, though ASD may be seen in patients of any race, ethnicity orsocioeconomic status, it is about four times more common among boys than girls.Epidemiological studies in the past fifty years suggest that the prevalence of ASD appears to beincreasing globally. This may very well be due to an increase in awareness, diagnostic criteriaexpansions, improved diagnostic tools and better reporting rather than an increase in incidence.CAUSESThe cause of ASD is not fully understood, but research suggests that multiple factors mayincrease the likelihood of developing ASD. Genetics are thought to be related, though thespecifics remain unclear. Older parents are more likely to have a child with autism. Parents whohave had a child with ASD are more likely to have another child diagnosed with ASD. Childrenwith twins who have ASD are also more likely to have ASD. Despite what is conveyed in themedia, one thing research has made very clear is that autism is not caused by vaccinationsMMR or otherwise.SYMPTOMSASD can cause significant difficulties with social skills, communication and behavioral issuesincluding restricted, repetitive behaviors, interests or activities. Patients with ASD may exhibitsymptoms such as: abnormal posture, facial expressions, tone of voice, lack of eye contact andbehavioral disturbances. They also may have deficits in communication including deficits inlanguage comprehension as well as speech.TREATMENTThere is currently no cure for ASD, although several interventions may be utilized. Behavioraltreatment and parent skills training programs are among the Evidence-Based PsychosocialInterventions that can be implemented to reduce difficulties in communication and socialbehaviour. These interventions also have a positive impact on the quality of life and well-beingfor persons with ASD and their caregivers. They do this by helping patients maximize functionand enable them to be more involved in the community. Quality Early Intervention is imperativeand can help to promote the optimal development and well-being of people with an ASD.NEED FOR NEW BIOMARKERS/ TREATMENTSThe diagnosis of ASD can be difficult as there is currently no medical diagnostic test availablethat can reliably diagnose ASD. Most patients are diagnosed after the age of four, although ASDcan reliably be diagnosed as early as age two. Early intervention with ASD has been shown toimprove outcomes and overall functioning and quality of life. It is important that more research isdone to help identify new biomarkers that can be used to diagnose ASD; both earlier as well asmore reliably. More research into this disorder could also help us to better understand thepathogenesis of ASD and possible treatment targets.METHODSBioinformatic analyses of the differentially expressed (whether increased or decreased) proteinswere compiled from various research articles. These are proteins that were identified in blood,saliva, or peripheral tissue samples as compared to controls. A total of 135 proteins fitting thisdescription were identified across twenty-one different studies. The genes that are responsiblefor encoding these proteins were then identified using the DAVID program. Next, the list ofentrez gene IDs were inputted into bioprophile.de to identify protein-protein interactionsamongst the gene IDs. Using the R spider database we identified protein-protein interactions.Following this, Cytoscape was used to visualize these interactions and pathways involved.Afterwards, Panther was used to model the functional classifications in the form of charts.RESULTS: (Major signaling pathways involved)Bioinformatic analyses of the differentially expressed proteins compiled from various researcharticles highlighted multiple major signaling pathways involving: integrin cell surface interactions,synaptic transmission, the citrate cycle (TCA cycle), metabolism of amino acids &amp; derivatives, aswell as integrin cell surface interactions, signaling by NGF, integration of energy metabolism,apoptosis, signaling by VEGF, signaling by notch, respiratory electron transport/ ATP synthesisby chemiosmotic coupling &amp; heat production by uncoupling proteins, signaling by insulinreceptors and synaptic transmission.NETWORK MODEL - CAPTIONS:Using the R Spider model several major signaling pathways have been identified as involved inthe proteomics of ASD. Model D1 shows the genes coding for the proteins are involved inintegrin cell surface interactions (P-value &lt;0.09). Model D2 shows involvement of synaptictransmission, the citrate cycle (TCA cycle), metabolism of amino acids &amp; derivatives, as well asintegrin cell surface interactions (P-value of &lt;0.005). Model D3 is the largest and most complexof the three. It shows many major signaling pathways are involved including: signaling by NGF,metabolism of amino acids &amp; derivatives, integration of energy metabolism, apoptosis, signalingby VEGF, signaling by notch, the citrate cycle, integrin cell surface interactions, respiratoryelectron transport/ ATP synthesis by chemiosmotic coupling &amp; heat production by uncouplingproteins, signaling by insulin receptors and synaptic transmission (P-value of &lt;0.065).CONCLUSION:Bioinformatic analyses of the differentially expressed proteins of each of these brain regionssuggests dysregulation of multiple pathways and protein interaction networks. The novelbiomarkers identified can be used after validation to better understand this condition anddesigning possible pharmacological interventions.Advocating Societies and Research Institutes:https://autismcanada.org/https://www.autism-society.org/https://www.autism.org/If you would like to learn more about autism please visit the links below:https://www.who.int/news-room/fact-sheets/detail/autism-spectrum-disordershttps://www.cdc.gov/ncbddd/autism/index.htmlNetwork Model D1Network Model D2Network Model D3<br><br><br><br><br><br><br><br>