Abstract Details

Title iPSC-generated motor neurons from patients with PTEN deficiency as a model to elucidate mechanisms underlying aberrant circuit development in autism spectrum disorder

Topic Child Neurology and Developmental Neurology

Presentation(s) P16 - Poster Session 16 (5:30 PM-6:30 PM)

Poster/Presentation
Number 5-009

Objective To provide better insight into molecular mechanisms of abnormal motor circuit development in patients with autism spectrum disorder (ASD) as well as mechanisms that may enhance neural repair following injury.

Background ASD is a pervasive neurodevelopmental disorder with genetic heterogeneity; the common endpoint being abnormal neural organization. Microtubule stability is essential to axon guidance, yet difficult to elucidate in models of ASD given limitations of in vivo systems. One of the few known single gene mutations that leads to an ASD phenotype is PTEN, which also causes macrocephaly due to accelerated early brain growth.

Design/Methods We use patient-derived PTEN mutant cell lines to develop alternative systems of studying the subcellular mechanisms of ASD impairments. PTEN regulates neural development and repair. Neurons that are PTEN-deficient have greater axonal extension and promote neural repair in a variety of lesion models. The loss of PTEN is known to enhance mTOR activity. In prior studies, we have found a link between mTOR activation, GSK3 beta inhibition and microtubule (MT) stability. Therefore, to both study mechanisms of neural repair and abnormal connectivity associated with ASD, we examined the effects of an ASD-associated PTEN mutation on axonal outgrowth in induced pluripotent stem cell-derived motor neurons.

Results We found that in control media, the PTEN mutant motor neurons tended to have smaller cell bodies, which was surprising, but longer neurites with fewer branch points compared to cells from parental controls. Neither treatment with the MT stabilizer Epothilone nor the GSK3 beta inhibitor CHIR 99021 had an effect on the PTEN mutant, but did, as expected, enhanced some parameters of neurite outgrowth.

Conclusions The effects of PTEN mutation either may not be mediated entirely by microtubule stabilization or these processes are maximally affected by the PTEN mutations. iPSC-derived motor neurons continue to have promise in identifying pathways important to the ASD phenotype.

Authors/Disclosures
Michelle Allen-sharpley, MD, PhD (Cedars-Sinai Medical Center Pediatric Neurology) PRESENTER	No disclosure on file
Michelle Allen-sharpley, MD, PhD (Cedars-Sinai Medical Center Pediatric Neurology)	No disclosure on file
	No disclosure on file
	No disclosure on file
Julian Martinez Agosto, MD, PhD (University of California Los Angeles)	Julian Martinez Agosto, MD, PhD has nothing to disclose.
	No disclosure on file
Harley I. Kornblum, MD, PhD (UCLA Sch of Med, Depts of Pharma & Peds)	No disclosure on file

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Abstract Details