Response of a Neuronal Model of Tuberous Sclerosis to Mammalian Target of Rapamycin (mTOR) Inhibitors: Effects on mTORC1 and Akt Signaling Lead to Improved Survival and Function

Meikle, Lynsey M.; Pollizzi, Kristen; Egnor, Anna; Kramvis, Ioannis; Lane, Heidi A.; Şahin, Mustafa; Kwiatkowski, David J.

doi:10.1523/jneurosci.0955-08.2008

Cited by 456 publications

(454 citation statements)

References 52 publications

(72 reference statements)

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“…We also show that this mechanism is dysregulated in TSC neurons. Figure 8 summarizes our working GST-synt ephrinB3 ΔPDZ P r e s e r u m a n t i-G Consistent with a human Golgi study 12 , mouse models of TSC have demonstrated dendritic spine abnormalities 13,39 . In particular, Tavazoie et al 13 showed that Tsc1 deficiency in cultured hippocampal slices led to decreased spine density, increased spine length and head width.…”

Section: Discussionsupporting

confidence: 61%

Rheb activation disrupts spine synapse formation through accumulation of syntenin in tuberous sclerosis complex

et al. 2015

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Rheb is a small GTP-binding protein and its GTPase activity is activated by the complex of Tsc1 and Tsc2 whose mutations cause tuberous sclerosis complex (TSC). We previously reported that cultured TSC neurons showed impaired spine synapse morphogenesis in an mTORC1-independent manner. Here we show that the PDZ protein syntenin preferentially binds to the GDP-bound form of Rheb. The levels of syntenin are significantly higher in TSC neurons than in wild-type neurons because the Rheb-GDP-syntenin complex is prone to proteasomal degradation. Accumulated syntenin in TSC neurons disrupts spine synapse formation through inhibition of the association between syndecan-2 and calcium/calmodulindependent serine protein kinase. Instead, syntenin enhances excitatory shaft synapse formation on dendrites by interacting with ephrinB3. Downregulation of syntenin in TSC neurons restores both spine and shaft synapse densities. These findings suggest that Rheb-syntenin signalling may be a novel therapeutic target for abnormalities in spine and shaft synapses in TSC neurons.

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Section: Discussionsupporting

confidence: 61%

Rheb activation disrupts spine synapse formation through accumulation of syntenin in tuberous sclerosis complex

et al. 2015

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“…It has been suggested that these brain malformations are dysplastic rather than neoplastic, which might explain why they are not responsive to the anti-proliferative effect of rapamycin (Bissler et al, 2008). However, pre-clinical studies in several mouse models showed improvement in neurological manifestations of TSC, such as seizures, and memory and learning deficits (Ehninger et al, 2008;Meikle et al, 2008;Zeng et al, 2008). Furthermore, reduced seizure frequencies in TSC patients have been described upon treatment with rapamycin (Franz et al, 2006;Muncy et al, 2009).…”

Section: The Mtorc1 Inhibitors As Treatment For Tscmentioning

confidence: 99%

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

et al. 2011

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The liver kinase B1 (LKB1)/adenosine mono-phosphateactivated protein kinase (AMPK)/tuberous sclerosis complex (TSC)/mammalian target of rapamycin (mTOR) complex (mTORC1) cassette constitutes a canonical signaling pathway that integrates information on the metabolic and nutrient status and translates this into regulation of cell growth. Alterations in this pathway are associated with a wide variety of cancers and hereditary hamartoma syndromes, diseases in which hyperactivation of mTORC1 has been described. Specific mTORC1 inhibitors have been developed for clinical use, and these drugs have been anticipated to provide efficient treatment for these diseases. In the present review, we provide an overview of the metabolic LKB1/AMPK/TSC/mTORC1 pathway, describe how its aberrant signaling associates with cancer development, and indicate the difficulties encountered when biochemical data are extrapolated to provide avenues for rational treatment of disease when targeting this signaling pathway. A careful examination of preclinical and clinical studies performed with rapamycin or derivatives thereof shows that although results are encouraging, we are only half way in the long and winding road to design rationale treatment targeted at the LKB1/ AMPK/TSC/mTORC1 pathway. Inherited cancer syndromes associated with this pathway such as the PeutzJeghers syndrome and TSC, provide perfect models to study the relationship between genetics and disease phenotype, and to delineate the complexities that underlie translation of biochemical and genetical information to clinical management, and thus provide important clues for devising novel rational medicine for cancerous diseases in general.

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“…Rapamycin, a potent autophagy inducer, improves myelination, leading to enhanced neuronal survival in tuberous sclerosis [89] . Meanwhile, in Long-Evans shaker rats, an increased autophagy level increases the number of myelinated axons and myelin sheath thickness during dysmyelination and demyelination, which implies that the autophagy pathway is a direct target for therapy for demyelination [90] .…”

mentioning

confidence: 99%

Role of autophagy in the pathogenesis of multiple sclerosis

Liang

2015

Neurosci. Bull.

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Autophagy plays an important role in maintaining the cellular homeostasis. One of its functions is to degrade unnecessary organelles and proteins for energy recycling or amino-acids for cell survival. Ablation of autophagy leads to neurodegeneration. Multiple sclerosis (MS), a permanent neurological impairment typical of chronic inflammatory demyelinating disorder, is an auto-immune disease of the central nervous system (CNS). Autophagy is tightly linked to the innate and adaptive immune systems during the autoimmune process, and several studies have shown that autophagy directly participates in the progress of MS or experimental autoimmune encephalomyelitis (EAE, a mouse model of MS). Dysfunction of mitochondria that intensively infl uences the autophagy pathway is one of the important factors in the pathogenesis of MS. Autophagy-related gene (ATG) 5 and immune-related GTPase M (IRGM) 1 are increased, while ATG16L2 is decreased, in T-cells in EAE and active relapsing-remitting MS brains. Administration of rapamycin, an inhibitor of mammalian target of rapamycin ( mTOR), ameliorates relapsing-remitting EAE. Infl ammation and oxidative stress are increased in MS lesions and EAE, but Lamp2 and the LC3-II/LC3-I ratio are decreased. Furthermore, autophagy in various glial cells plays important roles in regulating neuro-infl ammation in the CNS, implying potential roles in MS. In this review, we discuss the role of autophagy in the peripheral immune system and the CNS in neuroinfl ammation associated with the pathogenesis of MS. Keywords: autophagy; multiple sclerosis; neuro-infl ammation ·Review· IntroductionAutophagy, a lysosome-dependent degradation pathway, contributes to maintaining cellular homeostasis. Clearance of long-lived proteins, unnecessary organelles, and aggregate-prone proteins is mainly executed by autophagy for recycling cellular materials [1] . There are three subtypes of autophagy, macroautophagy, chaperone-mediated autophagy (CMA), and mitophagy. Macroautophagy is the major type for selective degradation of protein aggregates or misfolded proteins. The ubiquitin-labeled proteins are recognized by autophagy receptors, such as p62, neighbor of BRCA1 gene 1 (NBR1), and NIP3-like protein X (NIX), to form autophagosomes that then fuse with lysosomes for degradation. Many autophagy-related genes function during this process, such as Unc51-like kinase (ULK1) and autophagy-related gene (ATG) 5. Mammalian target of rapamycin (mTOR) represses autophagy by regulating ULK1 phosphorylation, while AMPK activates this process.CMA mediates the degradation of large molecular-weight proteins containing the KFERQ motif recognized by heat shock cognate protein of 70 kDa (HSC70). The substrate is then escorted to lysosome-associated membrane protein 2 (LAMP2A) for lysosomal degradation. Mitophagy is responsible for the degradation of damaged mitochondria.Parkin and PINK1 play critical roles in this process [2] . More Neurosci Bull August 1, 2015, 31(4): 435-444 436 attention has been paid to autophagy in the path...

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Response of a Neuronal Model of Tuberous Sclerosis to Mammalian Target of Rapamycin (mTOR) Inhibitors: Effects on mTORC1 and Akt Signaling Lead to Improved Survival and Function

Cited by 456 publications

References 52 publications

Rheb activation disrupts spine synapse formation through accumulation of syntenin in tuberous sclerosis complex

Rheb activation disrupts spine synapse formation through accumulation of syntenin in tuberous sclerosis complex

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

Role of autophagy in the pathogenesis of multiple sclerosis

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