Regulation and metabolic functions of mTORC1 and mTORC2

Physiological Reviews, Journal Year: 2021, Volume and Issue: 101(3), P. 1371 - 1426

Published: Feb. 18, 2021

Cells metabolize nutrients for biosynthetic and bioenergetic needs to fuel growth proliferation. The uptake of from the environment their intracellular metabolism is a highly controlled process that involves cross talk between signaling metabolic pathways. Despite constant fluctuations in nutrient availability environmental signals, normal cells restore homeostasis maintain cellular functions prevent disease. A central molecule integrates with mechanistic target rapamycin (mTOR). mTOR protein kinase responds levels signals. forms two complexes, mTORC1, which sensitive rapamycin, mTORC2, not directly inhibited by this drug. Rapamycin has facilitated discovery various mTORC1 metabolism. Genetic models disrupt either or mTORC2 have expanded our knowledge cellular, tissue, as well systemic Nevertheless, regulation particularly metabolism, lagged behind. Since an important cancer, aging, other metabolism-related pathologies, understanding distinct overlapping complexes vital development more effective therapeutic strategies. This review discusses key discoveries recent findings on complexes. We highlight cancer but also discuss examples mTOR-mediated reprogramming occurring stem immune cells, type 2 diabetes/obesity, neurodegenerative disorders, aging.

Language: Английский

---

Intranasal Delivery of Mesenchymal Stem Cell Derived Exosomes Loaded with Phosphatase and Tensin Homolog siRNA Repairs Complete Spinal Cord Injury

ACS Nano, Journal Year: 2019, Volume and Issue: 13(9), P. 10015 - 10028

Published: Aug. 27, 2019

Individuals with spinal cord injury (SCI) usually suffer from permanent neurological deficits, while spontaneous recovery and therapeutic efficacy are limited. Here, we demonstrate that when given intranasally, exosomes derived mesenchymal stem cells (MSC-Exo) could pass the blood brain barrier migrate to injured area. Furthermore, MSC-Exo loaded phosphatase tensin homolog small interfering RNA (ExoPTEN) attenuate expression of PTEN in region following intranasal administrations. In addition, considerably enhanced axonal growth neovascularization, reducing microgliosis astrogliosis. The ExoPTEN therapy also partly improve structural electrophysiological function and, most importantly, significantly elicited functional rats complete SCI. results imply may be used clinically promote for SCI individuals.

Language: Английский

---

Intracellular mRNA transport and localized translation

Nature Reviews Molecular Cell Biology, Journal Year: 2021, Volume and Issue: 22(7), P. 483 - 504

Published: April 9, 2021

Language: Английский

---

Peripheral Nerve Regeneration and Muscle Reinnervation

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(22), P. 8652 - 8652

Published: Nov. 17, 2020

Injured peripheral nerves but not central have the capacity to regenerate and reinnervate their target organs. After two most severe nerve injuries of six types, crush transection injuries, fibers distal injury site undergo Wallerian degeneration. The denervated Schwann cells (SCs) proliferate, elongate line endoneurial tubes guide support regenerating axons. axons emerge from stump viable attached neuronal soma. SCs downregulate myelin-associated genes concurrently, upregulate growth-associated that include neurotrophic factors as do injured neurons. However, gene expression is transient progressively fails axon regeneration within SC-containing tubes. Moreover, despite some preference motor sensory “find” appropriate pathways, fail enter original organs, obstacles functional recovery confront surgeons. Several surgical manipulations in clinical use, including tendon transfers, potential for brief low-frequency electrical stimulation proximal repair, local FK506 application accelerate outgrowth, are encouraging continuing research elucidate molecular basis regeneration.

Language: Английский

---

The translational landscape in spinal cord injury: focus on neuroplasticity and regeneration

Nature Reviews Neurology, Journal Year: 2019, Volume and Issue: 15(12), P. 732 - 745

Published: Nov. 14, 2019

Language: Английский

---

Context-specific regulation and function of mRNA alternative polyadenylation

Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 23(12), P. 779 - 796

Published: July 7, 2022

Language: Английский

---

Central nervous system regeneration

Cell, Journal Year: 2022, Volume and Issue: 185(1), P. 77 - 94

Published: Jan. 1, 2022

Language: Английский

---

The science of puromycin: From studies of ribosome function to applications in biotechnology

Computational and Structural Biotechnology Journal, Journal Year: 2020, Volume and Issue: 18, P. 1074 - 1083

Published: Jan. 1, 2020

Puromycin is a naturally occurring aminonucleoside antibiotic that inhibits protein synthesis by ribosome-catalyzed incorporation into the C-terminus of elongating nascent chains, blocking further extension and resulting in premature termination translation. It most commonly known as selection marker for cell lines genetically engineered to express resistance transgene, but its additional uses probe have proven invaluable across wide variety model systems, ranging from purified ribosomes cell-free translation intact cultured cells whole animals. comprised nucleoside covalently bound an amino acid, mimicking 3′ end aminoacylated tRNAs participate delivery acids ribosomes. Both moieties can tolerate some chemical substitutions modifications without significant loss activity, generating diverse toolbox puromycin-based reagents with added functionality, such biotin affinity purification or fluorophores fluorescent microscopy detection. These reagents, well anti-puromycin antibodies, played pivotal role advancing our understanding regulation dysregulation normal pathological processes, including immune response neurological function. This manuscript reviews current state research, structure mechanism action, relevant derivatives, use advanced methodologies major insights generated using techniques both lab clinic.

Language: Английский

---

Regulation of axonal regeneration after mammalian spinal cord injury

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 24(6), P. 396 - 413

Published: Jan. 5, 2023

Language: Английский

---

Axonal TDP-43 condensates drive neuromuscular junction disruption through inhibition of local synthesis of nuclear encoded mitochondrial proteins

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Nov. 25, 2021

Mislocalization of the predominantly nuclear RNA/DNA binding protein, TDP-43, occurs in motor neurons ~95% amyotrophic lateral sclerosis (ALS) patients, but contribution axonal TDP-43 to this neurodegenerative disease is unclear. Here, we show accumulation intra-muscular nerves from ALS patients and axons human iPSC-derived patient, as well neuromuscular junctions (NMJs) a mislocalization mouse model. In axons, hyper-phosphorylated promotes G3BP1-positive ribonucleoprotein (RNP) condensate assembly, consequently inhibiting local protein synthesis distal NMJs. Specifically, synaptic levels nuclear-encoded mitochondrial proteins are reduced. Clearance or dissociation G3BP1 condensates restored translation resolved TDP-43-derived toxicity both These findings support an gain function ALS, which can be targeted for therapeutic development.

Language: Английский

---