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Phenotypic Screen with TSC-Deficient Neurons Reveals Heat-Shock Machinery as a Druggable Pathway for mTORC1 and

Alessia Di Nardo1, Isadora Lenoël1, Kellen D Winden1

  • 1F.M. Kirby Neurobiology Center, Translational Neuroscience Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Cell Reports
|June 25, 2020
PubMed

Insights

Tuberous sclerosis complex (TSC) involves elevated mTORC1 signaling, which impairs neuronal cilia. Heat shock protein 90 (Hsp90) inhibition restores ciliation in TSC, offering a potential therapeutic target.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Genetics

Background:

  • Tuberous sclerosis complex (TSC) is a neurogenetic disorder characterized by elevated mechanistic targeting of rapamycin complex 1 (mTORC1) activity.
  • Ciliary deficits are linked to neurodevelopmental disorders, and mTORC1 signaling can impact cilia.

Purpose of the Study:

  • To investigate the effect of TSC on neuronal cilia.
  • To identify mechanisms linking mTORC1 hyperactivity to ciliary dysfunction in TSC.
  • To discover therapeutic strategies for restoring ciliation in TSC.

Main Methods:

  • Analysis of cortical tubers from TSC patients and TSC mouse models.
  • High-content image-based assays to quantify ciliation.
  • Phenotypic screening of mTORC1 inhibitors in TSC1/2-deficient neurons.
  • Investigation of heat shock protein 90 (Hsp90) inhibitors.

Main Results:

  • Cortical tubers from TSC patients and mutant mice exhibit reduced neuronal cilia.
  • mTORC1 activity inversely correlates with ciliation in TSC1/2-deficient neurons.
  • Inhibitors of Hsp90 suppress mTORC1 by regulating PI3K/Akt signaling.
  • Pharmacological inhibition of Hsp90 rescues ciliation via Hsp27 downregulation.

Conclusions:

  • Neuronal cilia are impaired in Tuberous Sclerosis Complex due to elevated mTORC1 activity.
  • Heat shock protein 90 (Hsp90) inhibition represents a druggable target to restore ciliation in TSC.
  • This study provides platforms for further research into TSC-related neuronal dysfunction.
Keywords:
17-AGGHsp27Hsp90TSCautismbrainciliaciliopathymTOR

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