# Dissecting the Role of Translation Mechanisms Downstream of mTORC1 in TSC Neuropathogenesis

> **NIH NIH R21** · YALE UNIVERSITY · 2021 · $460,628

## Abstract

ABSTRACT
Tuberous sclerosis complex (TSC) is a complex genetic disorder that commonly leads to
intractable epilepsies, cognitive dysfunction and autism. These clinical features are associated
with cortical malformations and neuron overgrowth. The underlying molecular mechanisms are
only partially understood, but essentially all cases of TSC are linked to mutations in the TSC1
and TSC2 genes. In normal cells, TSC1 and 2 form a complex that represses the mTOR
Complex 1 (mTORC1) signaling pathway, a master regulatory of cell growth. Loss-of-function
mutations in TSC1 or 2 lead to mTORC1 hyper-activation, which is considered the primary
driver of disease. It is less clear how mechanisms downstream of mTORC1 are involved in TSC
pathology. Recent evidence suggests a critical role for deregulation of mRNA translation, but
which mRNAs are deregulated and what molecular mechanisms control them are poorly
understood. We previously showed that mTORC1 primarily controls the translation of hundreds
of mRNAs that are defined by terminal oligopyrimidine (TOP) motifs. More recently, we found
that these are controlled through a translation repressor called La-related protein 1 (LARP1). In
this study, we propose to use a combination of RNA-seq and bioinformatic strategies to first
map the mTORC1-regulated translation landscape of normal and TSC primary mouse cortical
neurons, and determine which mRNAs are controlled through LARP1-dependent and
independent mechanisms (Aim 1). We will then determine in mice whether inactivation of
LARP1 promotes neurodevelopmental phenotypes that characterize TSC, including cortical
neuron misplacement and neuron overgrowth (Aim 2). Completion of these aims will
comprehensively identify mRNAs whose translation is deregulated in TSC, and test our
hypothesis that deregulated translation of TOP mRNAs is a primary driver of TSC pathology.
These insights will clarify our understanding of the mechanisms that give rise to TSC pathology
in the brain, guiding the development of more effective therapies. They are also likely relevant to
understanding other neurologic disorders associated with mTORC1 hyper-activation, including a
spectrum of familial epilepsies.

## Key facts

- **NIH application ID:** 10217433
- **Project number:** 1R21NS118616-01A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Carson Cornell Thoreen
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $460,628
- **Award type:** 1
- **Project period:** 2021-04-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10217433

## Citation

> US National Institutes of Health, RePORTER application 10217433, Dissecting the Role of Translation Mechanisms Downstream of mTORC1 in TSC Neuropathogenesis (1R21NS118616-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10217433. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*