Related Experiment Video

Updated: Apr 28, 2026

Spatio-Temporal Manipulation of Small GTPase Activity at Subcellular Level and on Timescale of Seconds in Living Cells
10:27

Spatio-Temporal Manipulation of Small GTPase Activity at Subcellular Level and on Timescale of Seconds in Living Cells

Published on: March 9, 2012

10.3K

Activation of Rheb, but not of mTORC1, impairs spine synapse morphogenesis in tuberous sclerosis complex

Shin Yasuda1, Hiroko Sugiura1, Shutaro Katsurabayashi2

  • 11] Neural Plasticity Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan [2].

Scientific Reports
|June 4, 2014
PubMed

Insights

Tuberous sclerosis complex (TSC) involves mutations affecting Rheb activation, not mTORC1 signaling, leading to impaired dendritic spine formation in neurons. This finding offers new therapeutic targets for TSC neurological symptoms.

Area of Science:

  • Neuroscience
  • Genetics
  • Cell Biology

Background:

  • Tuberous sclerosis complex (TSC) results from mutations in Tsc1 or Tsc2 genes.
  • The Tsc1/Tsc2 complex normally inhibits mammalian target of rapamycin complex 1 (mTORC1) signaling via Rheb-GTPase.
  • Dendritic spine abnormalities are a hallmark of neurological dysfunction in TSC.

Purpose of the Study:

  • To investigate the specific molecular mechanisms underlying impaired dendritic spine formation in Tsc2(+/-) neurons.
  • To determine the roles of mTORC1 signaling and Rheb activation in TSC-associated spinogenesis defects.

Main Methods:

  • Utilized Tsc2(+/-) mouse neurons and wild-type (WT) neurons.
  • Administered mTORC1 inhibitors and performed mTOR knockdown.
  • Expressed constitutively active and inactive Rheb variants in neurons.
  • Applied farnesyl transferase inhibitors to modulate Rheb activity.

Main Results:

  • Tsc2(+/-) neurons exhibited impaired dendritic spine formation, unresponsive to mTORC1 inhibition or mTOR knockdown.
  • Expression of active Rheb abolished spine formation in WT neurons.
  • Inactive Rheb rescued spine formation defects in Tsc2(+/-) neurons.
  • Rheb inactivation using farnesyl transferase inhibitors restored dendritic spine morphogenesis in Tsc2(+/-) neurons.

Conclusions:

  • Dendritic spine abnormalities in TSC are primarily driven by Rheb activation, not by dysregulation of mTORC1 signaling.
  • Targeting Rheb activity presents a potential therapeutic strategy for neurological manifestations of TSC.

More Related Videos

Measuring Transcellular Interactions through Protein Aggregation in a Heterologous Cell System04:47

Measuring Transcellular Interactions through Protein Aggregation in a Heterologous Cell System

Published on: May 22, 2020

2.7K
An Adoptive Transfer Model of Rheumatoid Arthritis in Mice07:37

An Adoptive Transfer Model of Rheumatoid Arthritis in Mice

Published on: June 6, 2025

1.5K

Related Concept Videos

TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors...
7.2K
Enzyme-linked Receptors01:00

Enzyme-linked Receptors

Enzyme-linked receptors are proteins that act as both receptor and enzyme, activating multiple intracellular signals. This is a large group of receptors that include the receptor tyrosine kinase (RTK) family. Many growth factors and hormones bind to and activate the RTKs.
Neurotrophin (NT) receptors are a family of RTKs, including trkA, trkB, and trkC (tropomyosin-related kinase) receptors. TrkA is specific for nerve growth factor (NGF), neurotrophin-6, and neurotrophin-7. TrkB binds...
64.6K
The Ras Gene02:38

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a...
5.7K
Rab Cascades01:25

Rab Cascades

Rab GTPases act in a regulated cascade during membrane fusion, helping the lipid bilayers mix. The Rab family of proteins are active when bound to GTP, and inactive when bound to GDP. Hence, they act as guanine nucleotide-dependent molecular switches. Rab-GTP recognizes and binds to long or short-range tethering proteins to capture the target vesicle. These tethers coordinate with SNAREs on the vesicle and the target membrane to assemble the trans SNARE complex that locks the mixing bilayers.
2.8K
T Cell Types and Functions01:24

T Cell Types and Functions

When T cells with CD4 markers are activated, they give rise to two types of effector cells: helper T cells and regulatory T cells. Meanwhile, T cells with CD8 markers differentiate into effector cytotoxic T cells. The differentiation of CD4 T cells into helper T cell subsets, such as Th1, Th2, and Th17 cells, is dependent on the antigen type, antigen-presenting cell, and regulatory cytokines.
Th1 cells stimulate dendritic cells to express necessary co-stimulatory molecules on their surfaces for...
3.2K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
5.1K