bims-tubesc 2023-01-22 papers

Issue of 2023‒01‒22
three papers selected by
Marti Cadena Sandoval
Columbia University

Cureus. 2022 Dec;14(12): e32663

Periodontoid Pseudotumor in Tuberous Sclerosis Associated With Neck Diffuse Lipomatosis.

Eduarda Pinto, Marcos Veiga, Amets Sagarribay, Carla Conceição.

Tuberous sclerosis (TS) is a genetic multisystem disorder associated with the development of benign tumors in many organs. Diffuse lipomatosis, which represents the overgrowth of fatty tissue in one part of the body, is a very rare finding reported in patients with tuberous sclerosis. We describe the case of a patient with diffuse lipomatosis in the right scapular, posterior cervical and perivertebral regions, associated with a space-occupying lesion adjacent to the odontoid process of C2 that appeared to be a pseudotumor, and discuss possible relation between these entities.

Keywords: diffuse lipomatosis; neuroradiology; periodontoid pseudotumor; phakomatoses; tuberous sclerosis

DOI: https://doi.org/10.7759/cureus.32663

Adv Biol Regul. 2022 Dec 31. pii: S2212-4926(22)00086-0. [Epub ahead of print] 100946

Defining the role of mTOR pathway in the regulation of stem cells of glioblastoma.

Meena Jhanwar-Uniyal, Olivia Gellerson, Julie Bree, Mohan Das, George Kleinman, Chirag D Gandhi.

The mechanistic target of rapamycin (mTOR), a serine/threonine kinase, functions by forming two multiprotein complexes termed mTORC1 and mTORC2. Glioblastoma (GBM) is a uniformly fatal brain tumor that remains incurable partly due to the existence of untreatable cancer stem cells (CSC). The pathogenesis of GBM is largely due to the loss of the tumor suppressor gene PTEN, which is implicated in the aberrant activation of the mTOR pathway. The major cause of tumor recurrence, growth, and invasion is the presence of the unique population of CSC. Resistance to conventional therapies appears to be caused by both extensive genetic abnormalities and dysregulation of the transcription landscape. Consequently, CSCs have emerged as targets of interest in new treatment paradigms. Evidence suggests that inhibition of the mTOR pathway can also be applied to target CSCs. Here we explored the role of the mTOR pathway in the regulation of stem cells of GBM by treating them with inhibitors of canonical PI3K/AKT/mTOR pathways such as rapamycin (mTORC1 inhibitor), PP242 (ATP binding mTORC1/2 inhibitor), LY294002 (PI3K inhibitor), and MAPK inhibitor, U0126. A significant number of GBM tumors expressed stem cell marker nestin and activated mTOR (pmTORSer2448), with most tumor cells co-expressing both markers. The expression of stem cell marker NANOG was suppressed following rapamycin treatment. The neurospheres were disrupted following rapamycin and LY294002 treatments. Rapamycin or PP242 along with differentiating agent All-trans-retinoic acid reduced stem cell proliferation. Treatment with novel small molecule inhibitors of mTORC1/2 demonstrated that Torin1 and Torin2 suppressed the proliferation of GBM CSC, while XL388 was less effective. Torin1 and XL388 delay the process of self-renewal as compared to controls, whereas Torin2 halted self-renewal. Torin2 was able to eradicate tumor cells. In conclusion, Torin2 effectively targeted CSCs of GBM by halting self-renewal and inhibiting cell proliferation, underscoring the use of Torin2 in the treatment of GBM.

Keywords: Glioblastoma; Stem cell; mTOR; mTORC1; mTORC2

DOI: https://doi.org/10.1016/j.jbior.2022.100946

Mol Brain. 2023 Jan 18. 16(1): 9

Cell-type-specific translational control of spatial working memory by the cap-binding protein 4EHP.

Shane Wiebe, Ziying Huang, Reese Jalal Ladak, Agnieszka Skalecka, Roberta Cagnetta, Jean-Claude Lacaille, Argel Aguilar-Valles, Nahum Sonenberg.

The consolidation of learned information into long-lasting memories requires the strengthening of synaptic connections through de novo protein synthesis. Translation initiation factors play a cardinal role in gating the production of new proteins thereby regulating memory formation. Both positive and negative regulators of translation play a critical role in learning and memory consolidation. The eukaryotic initiation factor 4E (eIF4E) homologous protein (4EHP, encoded by the gene Eif4e2) is a pivotal negative regulator of translation but its role in learning and memory is unknown. To address this gap in knowledge, we generated excitatory (glutamatergic: CaMKIIα-positive) and inhibitory (GABAergic: GAD65-positive) conditional knockout mice for 4EHP, which were analyzed in various behavioral memory tasks. Knockout of 4EHP in Camk2a-expressing neurons (4EHP-cKOexc) did not impact long-term memory in either contextual fear conditioning or Morris water maze tasks. Similarly, long-term contextual fear memory was not altered in Gad2-directed 4EHP knockout mice (4EHP-cKOinh). However, when subjected to a short-term T-maze working memory task, both mouse models exhibited impaired cognition. We therefore tested the hypothesis that de novo protein synthesis plays a direct role in working memory. We discovered that phosphorylation of ribosomal protein S6, a measure of mTORC1 activity, is dramatically reduced in the CA1 hippocampus of 4EHP-cKOexc mice. Consistently, genetic reduction of mTORC1 activity in either excitatory or inhibitory neurons was sufficient to impair working memory. Taken together, these findings indicate that translational control by 4EHP and mTORC1 in both excitatory and inhibitory neurons are necessary for working memory.

Keywords: GABAergic neurons; Glutamatergic neurons; Mechanistic target of rapamycin complex 1 (mTORC1); eIF4E homologous protein (4EHP)

DOI: https://doi.org/10.1186/s13041-023-00995-2