Autism spectrum disorders (ASD) now affect an astounding 1 in every 88 children in America (CDC Report, 2012). Individuals with ASD show symptoms that include deficits in communication and social interactions as well as repetitive behaviors. A number of genes associated with synapse formation and function are mutated in patients with ASD, suggesting autism is a disorder of the synapse. ASD is a debilitating lifelong medical condition for patients and their caregivers, so finding new ways to diagnose, treat and prevent ASD remains one of the biggest challenges in neuroscience. In unpublished studies, we made a revolutionary discovery that directly addresses this challenge. Specifically, we found that a single molecular mechanism-transcription elongation-can be directly linked to expression of a large number (>34) of synapse-associated ASD candidate genes. Elongation is the process where RNA polymerase II, in coordination with numerous elongation factors, traverses DNA to generate a gene transcript. This process has never been studied in the context of any brain disease. Here, we will test the novel hypothesis that deficits in transcription elongation can reduce expression of ASD candidate genes and impair synapse function. This hypothesis is strongly supported by clinical data from ASD patients and by our unpublished experiments with cultured cortical neurons. To test this hypothesis, we will determine the extent to which genes associated with the elongation machinery regulate a) expression of numerous ASD candidate genes, b) synapse function and c) ASD-like behaviors in mouse models. We noticed that at least 10 genes associated with transcription elongation are mutated in patients with ASD. We will determine the extent to which these 10 mutations impair transcription elongation and expression of known ASD genes in neurons. Lastly, we describe a novel approach that will allow us to identify chemicals commonly found in the environment that impair

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
1DP1ES024088-01
Application #
8560195
Study Section
Special Emphasis Panel (ZRG1-BCMB-N (50))
Program Officer
Lawler, Cindy P
Project Start
2013-09-30
Project End
2018-07-31
Budget Start
2013-09-30
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$760,000
Indirect Cost
$260,000
Name
University of North Carolina Chapel Hill
Department
Physiology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Tuttle, Alexander H; Molinaro, Mark J; Jethwa, Jasmine F et al. (2018) A deep neural network to assess spontaneous pain from mouse facial expressions. Mol Pain 14:1744806918763658
McCoy, Eric S; Taylor-Blake, Bonnie; Aita, Megumi et al. (2017) Enhanced Nociception in Angelman Syndrome Model Mice. J Neurosci 37:10230-10239
Piven, J; Elison, J T; Zylka, M J (2017) Toward a conceptual framework for early brain and behavior development in autism. Mol Psychiatry 22:1385-1394
Yi, Jason J; Paranjape, Smita R; Walker, Matthew P et al. (2017) The autism-linked UBE3A T485A mutant E3 ubiquitin ligase activates the Wnt/?-catenin pathway by inhibiting the proteasome. J Biol Chem 292:12503-12515
Tuttle, Alexander H; Bartsch, Victoria B; Zylka, Mark J (2016) The Troubled Touch of Autism. Cell 166:273-274
Mabb, Angela M; Simon, Jeremy M; King, Ian F et al. (2016) Topoisomerase 1 Regulates Gene Expression in Neurons through Cleavage Complex-Dependent and -Independent Mechanisms. PLoS One 11:e0156439
Pearson, Brandon L; Simon, Jeremy M; McCoy, Eric S et al. (2016) Identification of chemicals that mimic transcriptional changes associated with autism, brain aging and neurodegeneration. Nat Commun 7:11173
Zylka, Mark J; Simon, Jeremy M; Philpot, Benjamin D (2015) Gene length matters in neurons. Neuron 86:353-5
Ehlen, J Christopher; Jones, Kelly A; Pinckney, Lennisha et al. (2015) Maternal Ube3a Loss Disrupts Sleep Homeostasis But Leaves Circadian Rhythmicity Largely Intact. J Neurosci 35:13587-98
Yi, Jason J; Berrios, Janet; Newbern, Jason M et al. (2015) An Autism-Linked Mutation Disables Phosphorylation Control of UBE3A. Cell 162:795-807

Showing the most recent 10 out of 12 publications