Universitat Autònoma de Barcelona. Facultat de Biociències

Vila de la Puente, Carla

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Normal brain                              ASD brain Molecular Basis of Autism Spectrum Disorders   Carla Vila de la Puente Biomedical Science Degree, 2013   Methodology    First search of books, official websites, and Pubmed database reviews to get the basic principles. After that, Pubmed database original articles and important reviews were selected based on the journal impact and the date of publication. ASD biomarkers   Hyperserotonemia.  Immune system dysfunction.  Decreased GABA receptor  Increased ratio of excitation to inhibition.  Abnormal rate of symmetric brain growth.  Altered brain region size (amygdale, striatal nucleus).  Mitochondrial dysfunction.   Structural abnormalities in the “social brain”:            Physiopathology    Neurobiological basis of  ASD: altered patterns of neural connectivity  reduced long-range functional connectivity in the cortex and enhanced local connectivity in multiple brain regions.    Factors  Principal genes associated with high for ASD (susceptibility genes):   Figure 1. ASD main characteristics (Adapted from http://parentinghealthybabies.com/autism-spectrum-discorder-asd-in-children/).  Figure 2. Areas of the “social brain” (Adapted from Gotts et al., 2012)    Environmental factors examples: pesticides, air pollution, drugs, paternal age, maternal nutritional status, etc.   Current treatment    The principal treatments for ASD now a days, are based on behavioral interventions  ABA.  A wide variety of potential interventions for ASD have been championed, but few have been subjected to the rigors of controlled clinical trials.   Data shows all this available treatments for ASDs have an inconsistent efficacy.   Introduction   Leo Kanner in 1943 identifies four main characteristics of Autism:  Inability to relate well with people.  Serious difficulties in communication and language development.  Persistent insistence on sameness.  Early onset of the disorder, which is evident in the first three years of life.   According to DMS-V, ASD is a group of 4 developmental disorders with symptoms that are seen on a continuum ranging from mild to severe expression.                 Heterogeneous as notable for its variability as for its features.    Thirty years ago autism was very rare (4 of 10.000) but today ASD prevalence range is at about 0.6%-0.8% in preschool children and 1% in school children and adults. Objectives   Provide an overview of the main characteristics of ASD.  Emphasize in the genetic alterations and their pathways related to ASD fisiopathology.  Etiology   ASD is a complex human genetic disorder that involves interactions between genes and environment: Figure 3. Complexity of gene and environment interactions in ASD (Adapted from Schwartzer et al., 2012)   Table 1. Genes associated with ASD (Adapted from Toro et al., 2010). Genes Chromosome Function Evidence FMR1 Xq27 Synaptic translation Mutations MECP2  Xq26 Chromatin remodeling CNV, mutations TSC1  9q24.13 mTOR/PI3K pathway CNV, mutations TSC2 16p13.3 mTOR/PI3K pathway CNV, mutations NF1 17q11.2 mTOR/PI3K pathway CNV, mutations PTEN 10q23.31 mTOR/PI3K pathway CNV, mutations RFWD2 1q25.2-q25.2 Ubiquitination CNV NRXN1 2p16.3 Synaptic CAM CNV, mutations, SNP CNTN4 3p26.3 Synaptic CAM CNV MEF2C 5q14.3 Transcription factor CNV, mutations SYNGAP1 6p21.3 Synaptic Ras GAP CNV CNTNAP2 7q35-7q36.1 Synaptic CAM CNV, rare variantsa UBE3A 15q11-q13 Ubiquitination CNV SHANK3 22q13 Synaptic scaffold CNV, mutations NLGN3 Xq13.1 Synaptic CAM Mutation NLGN4 Xp22 Synaptic CAM CNV, mutations GRIA3 Xp25 Synaptic receptor CNV SEMA5A 5p15.2 Axonal guidance  SNP MET 7q31.2 Tyrosin kinase SNP PARK2 6q26 Ubiquitination CNV FBXO40 3q13.3  Unknown function CNV Figure 4. Potential effects of network connectivity patterns on brain activation (Adapted from Belmonte et al., 2004).    Figure 5. Steps for the generation of new (cortical) neurons (Adapted from Maurer et al., 2012).      Changes in ASD connectivity could be due to:  1. Dendrite spine growth 2. Synapse formation and stabilization  Figure 6. Lifetime trajectory of dendritic spine number in ASD (pink) (Adapted from Penzes et al., 2011).   Figure 7. The potential relationship of ASD genes to synaptic function. (Adapted from Walsh, 2008).    2.2. mTOR/PI3K pathway  TSC1/TSC2, NF1 and PTEN  2.3. Ubiquitination  UBE3A 2.4. Abnormal level of transcription regulatory proteins   MECP2 and FMR1   2.1. Synaptic adhesion proteins     Figure 8. The MET and mTOR/PI3K pathway, and genes implicated in ASD risk (Adapted from Kelleher and Bear, 2008).    Figure 9. UBEA, Arc, and AMPAR endocytosis and UBE3A  mutation causing ASD (Adapted from Tai and Shuman, 2010) .    Conclusions    Impaired neuronal network connectivity strongly indicates the basis of behavioral and cognitive abnormalities in ASD.   It is clear that ASD has a strong genetic component.   None of the current treatments are based upon a specific understanding of the causes of ASD.    FUTURE CHALLENGE: determine the signaling pathways in which disease risk genes function, in order to translate this knowledge into mechanism-based therapeutics.   

Molecular basis of autism spectrum disorders

http://ddd.uab.cat/pub/tfg/2013/113518/TFG_carlaviladelapuente.pdf

Molecular basis of autism spectrum disorders

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