# Disrupted ciliary signaling in the brain pathology of Tuberous Sclerosis Complex (Diversity Supplement)

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2022 · $65,950

## Abstract

Project Summary from Parent Award
Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder affecting several organs. Individuals with
TSC suffer from refractory epilepsy, intellectual disabilities and autism spectrum disorder, and the neurological
manifestations are often the most disabling for these patients. Central nervous system (CNS) manifestations
include disorganized brain connectivity, increased astrogliosis, and presence of immature dysmorphic neurons.
Despite the fact that increased mTORC1 activity has been clearly implicated in the brain manifestations of
TSC, a critical unmet medical need remains to identify the downstream molecular pathways implicated in the
abnormal brain development. Ciliopathies are genetic disorders caused by mutations in genes affecting
primary cilia which are sensory cellular antenna with a role in brain homeostasis and development, thought to
act as a key regulatory node for sonic hedgehog signaling. Ciliopathies encompass a range of genetic
disorders that share ciliary dysfunction and can affect several organs, including the brain. This proposal builds
on robust in vitro and in vivo data indicating that certain brain abnormalities of TSC recapitulate the
manifestations of ciliopathies with alteration in the Shh signaling pathway. In particular, we found reduced
ciliation in Tsc2-knockdown hippocampal neurons, in neuronal-specific Tsc1 and Tsc2 conditional knockout
mouse models and in the giant cells of the cortical tubers of TSC patients. Notably, defective ciliogenesis
was associated with an altered Shh signaling pathway and presence of immature neurons. To gain
insights into the molecular mechanism implicated in defective ciliation, we performed a phenotypic screen in
the Tsc2-deficient neurons and identified the heat shock protein hsp90 as a drug target that reverses altered
ciliation independently from mTORC1 hyperactivation. Using a high throughput cell-based assay, we
uncovered the existence of a therapeutic window for cilia restoration through hsp90 inhibition, without
affecting TORC1 activation. These findings enable us to build our central hypothesis that hsp90 is the
mTORC1 downstream target responsible for the ciliopathy-like phenotype seen in TSC. Here, we propose to
determine the mechanistic basis by which hsp90 inhibition restores cilia in Tsc2 deficient neurons using
multiple pharmacological and genetic techniques and by identifying the hsp90 interactome in the
TSC1/2 mutant neurons. Presence of immature neuronal properties, astrogliosis, and aberrant regulation of the
Shh pathway are some of the neuronal TSC manifestations that will be investigated to establish the functional
relevance of restoring cilia. Finally, we will first examine cilia in cortical neurons generated from TSC patient-
derived induced pluripotent stem cells (iPSCs) and their isogenic controls. We will perform preclinical
pharmacokinetics/pharmacodynamics (PK/PD) assessment of brain penetration and exposure of hsp9...

## Key facts

- **NIH application ID:** 10516328
- **Project number:** 3R01NS113591-03S1
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** MUSTAFA SAHIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $65,950
- **Award type:** 3
- **Project period:** 2022-01-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10516328

## Citation

> US National Institutes of Health, RePORTER application 10516328, Disrupted ciliary signaling in the brain pathology of Tuberous Sclerosis Complex (Diversity Supplement) (3R01NS113591-03S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10516328. Licensed CC0.

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