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Modeling Neurodevelopmental Deficits in Tuberous Sclerosis Complex with Stem Cell Derived Neural Precursors and Neurons

  • Maria Sundberg
  • Mustafa SahinEmail author
Chapter
Part of the Advances in Neurobiology book series (NEUROBIOL, volume 25)

Abstract

Tuberous sclerosis complex (TSC) is a rare genetic disorder that is caused by mutations in TSC1 or TSC2. TSC is a multi-organ disorder characterized by development of non-malignant cellular overgrowths, called hamartomas, in different organs of the body. TSC is also characterized as a neurodevelopmental disorder presenting with epilepsy and autism, and formation of cortical malformations (“tubers”), subependymal giant cell astrocytomas (SEGAs), and subependymal nodules (SENs) in the patient’s brain. In this chapter, we are going to give an overview of neural stem cell and neuronal development in TSC. In addition, we will also describe previously developed animal models of TSC that display seizures, autistic-like behaviors, and neuronal cell abnormalities in vivo, and we will compare them to disease phenotypes detected with human stem cell derived neuronal cells in vitro. We will describe the effects of TSC-mutations in different neural cell subtypes, and discuss the mitochondrial function, autophagy, and synaptic development and functional deficits in the neurons. Finally, we will review utilization of these human TSC-patient derived neuronal models for drug screening to develop new treatment options for the neurological phenotypes seen in TSC patients.

Keywords

Tuberous sclerosis complex Neural stem cells Autism Epilepsy mTORC1 mTORC2 Mitochondrion Astrogliosis Synaptogenesis 

Notes

Acknowledgements

Owing to limited space, we have not quoted all literature in the field, and we apologize to those whose articles are not referenced. We would like to thank Denise McGinnis for critical reading of the manuscript. We would like to thank Ville Kujala for design and preparation of the images. The Sahin lab has received grant funding from the US National Institutes of Health (NIH) (U01-NS082320, U01-NS092595, and U54-HD090255), US Department of Defense W81XWH-15–1–0189, Nancy Lurie Marks Family Foundation, Autism Speaks, TS Alliance, National Ataxia Foundation, Harvard Stem Cell Institute, Tommy Fuss Center, Roche, Novartis, Pfizer and LAM Therapeutics.

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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Department of NeurologyF.M. Kirby Center for Neurobiology, Boston Children’s Hospital, Harvard Medical SchoolBostonUSA

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