Mechanistic target of rapamycin complex 1 and 2 in human temporal lobe epilepsy

Talos, Delia M.; Jacobs, Leah; Gourmaud, Sarah; Coto, Carlos A.; Sun, Hongyu; Lim, Kuei-Cheng; Lucas, Timothy H.; Davis, Kathryn A.; Martinez‐Lage, Maria; Jensen, Frances E.

doi:10.1002/ana.25149

Cited by 66 publications

(47 citation statements)

References 95 publications

(359 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The mTORC1 and mTORC2 complexes are also upregulated in tissue from patients with MTLE 59 . Therefore, our findings strengthen the relevance of the mTOR pathway in the mechanisms underlying MTLE 60 .…”

Section: Discussionsupporting

confidence: 82%

Laser microdissection-based microproteomics of the hippocampus of a rat epilepsy model reveals regional differences in protein abundances

Canto

Vieira

Matos

et al. 2020

Sci Rep

View full text Add to dashboard Cite

cendes 8,9 & iscia Lopes-cendes 1,9* Mesial temporal lobe epilepsy (MTLE) is a chronic neurological disorder affecting almost 40% of adult patients with epilepsy. Hippocampal sclerosis (HS) is a common histopathological abnormality found in patients with MTLE. HS is characterised by extensive neuronal loss in different hippocampus subregions. In this study, we used laser microdissection-based microproteomics to determine the protein abundances in different regions and layers of the hippocampus dentate gyrus (DG) in an electric stimulation rodent model which displays classical HS damage similar to that found in patients with MTLE. Our results indicate that there are differences in the proteomic profiles of different layers (granule cell and molecular), as well as different regions, of the DG (ventral and dorsal). We have identified new signalling pathways and proteins present in specific layers and regions of the DG, such as PARK7, RACK1, and connexin 31/gap junction. We also found two major signalling pathways that are common to all layers and regions: inflammation and energy metabolism. Finally, our results highlight the utility of high-throughput microproteomics and spatial-limited isolation of tissues in the study of complex disorders to fully appreciate the large biological heterogeneity present in different cell populations within the central nervous system. Currently, it is well recognised that proteins and their biological roles are multifaceted and complex since all biological mechanisms rely on correct protein function. However, a major part of protein cellular machinery remains unknown, especially in disease-related processes. Therefore, studying proteins, specifically their presence and abundance, is relevant when addressing complex mechanisms leading to disease 1. Laser microdissection-based microproteomics allows for the study of the proteome of enriched specific cell types of interest obtained from a small amount of tissue (100 μg or less) 1-3. Epilepsy is a chronic neurological disorder affecting around 2% of the world population 27/02/2020 18:22:00. It presents a wide variety of clinic manifestations, aetiologies, severities, and prognoses. However, the occurrence of an epileptic seizure, caused by abnormal neuronal discharges, is the common feature of all types of epilepsy 4. Mesial temporal lobe epilepsy (MTLE) is the most frequent form in adults, present in 40% of patients with epilepsy, many of whom do not respond to clinical treatment 5-8 .

show abstract

Section: Discussionsupporting

confidence: 82%

Laser microdissection-based microproteomics of the hippocampus of a rat epilepsy model reveals regional differences in protein abundances

Canto

Vieira

Matos

et al. 2020

Sci Rep

View full text Add to dashboard Cite

show abstract

“…11,21,[33][34][35][36][37][38][39][40][41][42] Consistent with previous reports, we found low levels of baseline P-S6 immunoreactivity in control brain sections within scattered cortical neurons across all layers in the subpial region of layer I (Fig 4). 43,44 A similarly low level of baseline P-S6 labeling was observed in the SLC35A2-associated cases (see Fig 4), suggesting that SLC35A2 haploinsufficiency does not result in activation of mTOR signaling.…”

Section: Clinical Neuroimaging and Neuropathological Features Of Thmentioning

confidence: 62%

“…The presence of MRI appearance or pathological evidence of FCD in Cases 2 to 5 prompted assessment of increased mTOR activation, because classically FCDs have been associated with mTOR‐related genetic abnormalities . Consistent with previous reports, we found low levels of baseline P‐S6 immunoreactivity in control brain sections within scattered cortical neurons across all layers in the subpial region of layer I (Fig ) . A similarly low level of baseline P‐S6 labeling was observed in the SLC35A2 ‐associated cases (see Fig ), suggesting that SLC35A2 haploinsufficiency does not result in activation of mTOR signaling.…”

Section: Resultsmentioning

confidence: 99%

Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy

Winawer

Griffin

Samanamud

et al. 2018

Annals of Neurology

111

View full text Add to dashboard Cite

show abstract

“…However, detailed analysis of the EEG data did not reveal a difference in total number of seizures in the 2 h after drug injection compared to any of the other 2‐h windows within 24 h following injection. A second explanation could be that mTORC2 activation is neuroprotective instead and hence, a decrease in mTORC2 reduces the effectiveness of inhibiting mTORC1. The second specific drug that we tested, PF4708671, is a cell‐permeable inhibitor of p70 ribosomal S6 kinase (S6K1 isoform).…”

Section: Discussionmentioning

confidence: 99%

Effects of antiepileptic drugs in a new TSC/mTOR‐dependent epilepsy mouse model

Koene

Grondelle

Onori

et al. 2019

Ann Clin Transl Neurol

View full text Add to dashboard Cite

Objective An epilepsy mouse model for Tuberous Sclerosis Complex (TSC) was developed and validated to investigate the mechanisms underlying epileptogenesis. Furthermore, the possible antiepileptogenic properties of commonly used antiepileptic drugs (AEDs) and new compounds were assessed. Methods Tsc1 deletion was induced in CAMK2A‐expressing neurons of adult mice. The antiepileptogenic properties of commonly used AEDs and inhibitors of the mTOR pathways were assessed by EEG recordings and by molecular read outs. Results Mice developed epilepsy in a narrow time window (10 ± 2 days) upon Tsc1 gene deletion. Seizure frequency but not duration increased over time. Seizures were lethal within 18 days, were unpredictable, and did not correlate to seizure onset, length or frequency, reminiscent of sudden unexpected death in epilepsy (SUDEP). Tsc1 gene deletion resulted in a strong activation of the mTORC1 pathway, and both epileptogenesis and lethality could be entirely prevented by RHEB1 gene deletion or rapamycin treatment. However, other inhibitors of the mTOR pathway such as AZD8055 and PF4708671 were ineffective. Except for ketogenic diet, none of commonly used AEDs showed an effect on mTORC1 activity. Vigabatrin and ketogenic diet treatment were able to significantly delay seizure onset. In contrast, survival was shortened by lamotrigine. Interpretation This novel Tsc1 mouse model is highly suitable to assess the efficacy of antiepileptic and ‐epileptogenic drugs to treat mTORC1‐dependent epilepsy. Additionally, it allows us to study the mechanisms underlying mTORC1‐mediated epileptogenesis and SUDEP. We found that early treatment with vigabatrin was not able to prevent epilepsy, but significantly delayed seizure onset.

show abstract

Mechanistic target of rapamycin complex 1 and 2 in human temporal lobe epilepsy

Cited by 66 publications

References 95 publications

Laser microdissection-based microproteomics of the hippocampus of a rat epilepsy model reveals regional differences in protein abundances

Laser microdissection-based microproteomics of the hippocampus of a rat epilepsy model reveals regional differences in protein abundances

Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy

Effects of antiepileptic drugs in a new TSC/mTOR‐dependent epilepsy mouse model

Contact Info

Product

Resources

About