A novel rapamycin analog is highly selective for mTORC1 in vivo

Schreiber, Katherine H.; Apelo, Sebastian I. Arriola; Yu, Deyang; Brinkman, Jacqueline A.; Velarde, Michael C.; Syed, Faizan A.; Liao, Chen‐Yu; Baar, Emma L.; Carbajal, Kathryn; Sherman, Dawn S.; Ortiz, Denise; Brunauer, Regina; Yang, Shany E.; Tzannis, Stelios T.; Kennedy, Brian K.; Lamming, Dudley W.

doi:10.1038/s41467-019-11174-0

Cited by 154 publications

(84 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the applicability of this class of inhibitors is limited by poor bioavailability and toxic off-target inhibition of mTORC2, which may lead to insulin resistance and other complications (Lamming et al, 2012;Liu and Sabatini, 2020). The recent development of new-generation, mTORC1-specific inhibitors with more complete inhibitory profiles than rapamycin (Chung et al, 2019;Mahoney et al, 2018;Rodrik-Outmezguine et al, 2016;Schreiber et al, 2019) All authors read and edited the manuscript.…”

Section: Discussionmentioning

confidence: 99%

NPC1-mTORC1 signaling Couples Cholesterol Sensing to Organelle Homeostasis and is a Targetable Pathway in Niemann-Pick type C

Davis

Shin

Lim

et al. 2020

Preprint

View full text Add to dashboard Cite

Lysosomes promote cellular homeostasis through macromolecular hydrolysis within their lumen and metabolic signaling by the mTORC1 kinase on their limiting membranes. Both hydrolytic and signaling functions require precise regulation of lysosomal cholesterol content. In Niemann-Pick type C (NPC), loss of the cholesterol exporter, NPC1, causes cholesterol accumulation within lysosomes, leading to mTORC1 hyperactivation, disrupted mitochondrial function and neurodegeneration. The compositional and functional alterations in NPC lysosomes, and how aberrant cholesterol-mTORC1 signaling contributes to organelle pathogenesis are not understood. Through proteomic profiling of NPC lysosomes, we find pronounced proteolytic impairment compounded with hydrolase depletion and enhanced membrane damage. Genetic and pharmacologic mTORC1 inhibition restores lysosomal proteolysis without correcting cholesterol storage, implicating aberrant mTORC1 as a pathogenic driver downstream of cholesterol accumulation. Consistently, mTORC1 inhibition ameliorates mitochondrial dysfunction in a neuronal model of NPC. Thus, cholesterol-mTORC1 signaling controls organelle homeostasis and is a targetable pathway in NPC.

show abstract

Section: Discussionmentioning

confidence: 99%

NPC1-mTORC1 signaling Couples Cholesterol Sensing to Organelle Homeostasis and is a Targetable Pathway in Niemann-Pick type C

Davis

Shin

Lim

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Glucose tolerance test was performed as described previously 47 . Briefly, mice were deprived of food for 6 hours and then injected intraperitoneally (i.p.)…”

Section: Methodsmentioning

confidence: 99%

Brain-Specific Inhibition of mTORC1 by a Dual Drug Strategy: A Novel Approach for the Treatment of Alcohol Use Disorder

Ehinger

Zhang

Phamluong

et al. 2020

Preprint

View full text Add to dashboard Cite

Alcohol Use Disorder (AUD) is a devastating psychiatric disorder affecting a large portion of the population. Unfortunately, efficacious medications to treat the disease are limited and thus AUD represents an area of unmet medical need. mTORC1 plays a crucial role in neuroadaptations underlying alcohol use. mTORC1 also contributes to alcohol craving, habit, and relapse. Thus, mTORC1 inhibitors are promising therapeutic agents to treat AUD. However, chronic inhibition of mTORC1 in the periphery produces undesirable side effects in humans, which limit their potential clinical use for the treatment of AUD. To overcome these limitations, we utilized a binary drug strategy in which mice were co-administered the mTORC1 inhibitor RapaLink-1 together with a novel small molecule (RapaBlock) to protect mTORC1 activity in the periphery. We show that the dual administration of RapaLink-1 with RapaBlock, abolishes RapaLink-1-dependent mTORC1 inhibition in the liver and blocks adverse side effects detected in humans including body weight loss, glucose intolerance and liver toxicity. Importantly, we show that co-administration of RapaLink-1 and RapaBlock inhibits alcohol-dependent mTORC1 activation in the Nucleus Accumbens and robustly moderates the level of alcohol use. Our data present a novel approach that could be used to treat individuals suffering from AUD .

show abstract

“…Age-dependent knockdown of mTor (using in vivo RNAi 22 ) was achieved using the well-established conditional GeneSwitch system 23,24 , by feeding adult flies mifepristone (RU486). We chose RNAi over rapamycin treatment as genetic suppression of mTor signalling results in larger effects 4 and more potent rapalogs are currently being developed 25 . The ligand RU486 for GeneSwitch allows close experimental control of downstream genetic tools.…”

Section: Resultsmentioning

confidence: 99%

Age-dependent effects of reduced mTor signalling on life expectancy through distinct physiology

Simons

Hartshorne

Trooster

et al. 2019

Preprint

View full text Add to dashboard Cite

12Research on the mechanisms of ageing has identified ways via which lifespan can 13 be extended in model organisms, increasing the potential for translation of these 14 findings to our own species. However, the large majority of research on animal 15 models involves dietary, genetic or pharmacological treatments throughout life -16 limiting translational potential and ignoring age-dependent effects. Previously, we 17 have suggested using demographic meta-analysis that reduced mTor signalling has 18 the potential to instantly rejuvenate. We have now tested this prediction 19 experimentally using large-scale demographic data (N > 10,000) combined with 20 conditional knockdown of mTor in Drosophila melanogaster. Indeed, reduced mTor 21 decreased mortality rate when applied during old age. Interestingly, we found that 22 transient treatment during early adult life had long-lasting benefits. Age-dependent 23 deep-RNAseq indicated that these effects arose from distinct physiology and 24 implicate alternative splicing as a potential mechanism for the long-lasting benefits of 25 transient mTor reduction. These findings suggest that reducing mTor short term or 26 during old age could be used to combat ageing. In addition, our findings suggest that 27 the results from experimental research on mTor signalling, and potentially other 28 mechanisms of ageing, that employ life-long interventions are likely to be a complex 29 composite of age-dependent effects that counteract or enhance each other. 30 157 effects cox proportional hazard models correcting for cage effects (see methods 14,31 ). B) Transient 158 mTor knockdown (maximum induction of GeneSwitch at blue dotted line) resulted in a modest 159 increase in mortality during early life, but subsequently resulted in a sustained mortality reduction 160 throughout life (P < 0.0001). Similar effects were seen when mTor was knocked down continuously. 161The red dotted line now indicated when mTor in the transient treatment is back to control levels. 162These experiments were all ran together at the same time but are split in two panels for graphical 163 purposes. 342

show abstract

A novel rapamycin analog is highly selective for mTORC1 in vivo

Cited by 154 publications

References 70 publications

NPC1-mTORC1 signaling Couples Cholesterol Sensing to Organelle Homeostasis and is a Targetable Pathway in Niemann-Pick type C

NPC1-mTORC1 signaling Couples Cholesterol Sensing to Organelle Homeostasis and is a Targetable Pathway in Niemann-Pick type C

Brain-Specific Inhibition of mTORC1 by a Dual Drug Strategy: A Novel Approach for the Treatment of Alcohol Use Disorder

Age-dependent effects of reduced mTor signalling on life expectancy through distinct physiology

Contact Info

Product

Resources

About