bims-tubesc 2022-11-20 papers

Issue of 2022‒11‒20
five papers selected by
Marti Cadena Sandoval
Columbia University

Psychiatr Pol. 2022 May 03. pii: 146265. [Epub ahead of print] 1-20

Tuberous sclerosis complex-associated neuropsychiatric disorders.

Anna B Marcinkowska, Agnieszka Tarasewicz, Sergiusz Jóźwiak, Alicja Dębska-Ślizień, Edyta Szurowska.

The aim of the study was to provide a state-of-the-art review with regard to neuropsychiatric disorders associated with tuberous sclerosis complex (TSC). TSC is a rare genetic disease classified as a phacomatosis. Due to the wide spectrum of clinical symptoms of the disease, many cases remain undiagnosed. The vast majority of people with a mutation in the TSC1 or TSC2 genes develop some of the neuropsychiatric symptoms during their lifetime. Diagnostic criteria, neuroanatomical pathology and pathophysiology of psychiatric, neuropsychological, developmental and psychosocial symptoms present in TSC are described. The specificity of epilepsy in TSC and its role in neuropsychiatric and neuropsychological development are presented. All levels (intellectual, developmental, behavioral, psychiatric, school, neuropsychological and psychosocial) of tuberous sclerosis complex-associated neuropsychiatric disorders (TAND) are discussed in detail. The TAND Checklist - a tool for assessing all potentially disturbed aspects of functioning - was presented. The importance of proper diagnosis of neuropsychiatric disorders and multidisciplinary patient care was emphasized.

Keywords: tuberous sclerosis complex; tuberous sclerosis complex-associated neuropsychiatric disorders

DOI: https://doi.org/10.12740/PP/OnlineFirst/146265

iScience. 2022 Nov 18. 25(11): 105458

Reciprocal effects of mTOR inhibitors on pro-survival proteins dictate therapeutic responses in tuberous sclerosis complex.

Molly C McNamara, Aaron M Hosios, Margaret E Torrence, Ting Zhao, Cameron Fraser, Meghan Wilkinson, David J Kwiatkowski, Elizabeth P Henske, Chin-Lee Wu, Kristopher A Sarosiek, Alexander J Valvezan, Brendan D Manning.

mTORC1 is aberrantly activated in cancer and in the genetic tumor syndrome tuberous sclerosis complex (TSC), which is caused by loss-of-function mutations in the TSC complex, a negative regulator of mTORC1. Clinically approved mTORC1 inhibitors, such as rapamycin, elicit a cytostatic effect that fails to eliminate tumors and is rapidly reversible. We sought to determine the effects of mTORC1 on the core regulators of intrinsic apoptosis. In TSC2-deficient cells and tumors, we find that mTORC1 inhibitors shift cellular dependence from MCL-1 to BCL-2 and BCL-XL for survival, thereby altering susceptibility to BH3 mimetics that target specific pro-survival BCL-2 proteins. The BCL-2/BCL-XL inhibitor ABT-263 synergizes with rapamycin to induce apoptosis in TSC-deficient cells and in a mouse tumor model of TSC, resulting in a more complete and durable response. These data expose a therapeutic vulnerability in regulation of the apoptotic machinery downstream of mTORC1 that promotes a cytotoxic response to rapamycin.

Keywords: Biological sciences; Cancer; Cell biology; Molecular biology

DOI: https://doi.org/10.1016/j.isci.2022.105458

Ann Neurol. 2022 Nov 16.

Tubers affecting the fusiform face area are associated with autism diagnosis.

TACERN study group

OBJECTIVE: Tuberous Sclerosis Complex (TSC) is associated with focal brain "tubers" and a high incidence of autism spectrum disorder (ASD). The location of brain tubers associated with autism may provide insight into the neuroanatomical substrate of ASD symptoms.METHODS: We delineated tuber locations for 115 TSC participants with ASD (n = 31) and without ASD (n = 84) from the Tuberous Sclerosis Complex Autism Center of Excellence Research Network. We tested for associations between ASD diagnosis and tuber burden within the whole brain, specific lobes, and at eight regions of interest derived from the ASD neuroimaging literature including the anterior cingulate, orbitofrontal and posterior parietal cortices, the inferior frontal and fusiform gyri, the superior temporal sulcus, the amygdala, and the supplemental motor area. Next, we performed an unbiased data-driven voxel-wise lesion symptom mapping (VLSM) analysis. Finally, we calculated the risk of ASD associated with positive findings from the above analyses.
RESULTS: There were no significant ASD-related differences in tuber burden across the whole-brain, within specific lobes, or within a priori regions derived from the ASD literature. However, using VLSM analysis we found that tubers involving the right fusiform face area (FFA) were associated with a 3.7-fold increased risk of developing ASD.
INTERPRETATION: While TSC is a rare cause of ASD, there is a strong association between tuber involvement of the right FFA and ASD diagnosis. This highlights a potentially causative mechanism for developing autism in TSC that may guide research into ASD symptoms more generally. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/ana.26551

Cell Death Dis. 2022 Nov 18. 13(11): 972

Loss of myeloid Tsc2 predisposes to angiotensin II-induced aortic aneurysm formation in mice.

Xue Liu, Yan Liu, Rui-Xue Yang, Xiang-Jiu Ding, Er-Shun Liang.

RATIONALE: Genetic studies have proved the involvement of Tuberous sclerosis complex subunit 2 (Tsc2) in aortic aneurysm. However, the exact role of macrophage Tsc2 in the vascular system remains unclear. Here, we examined the potential function of macrophage Tsc2 in the development of aortic remodeling and aortic aneurysms.METHODS AND RESULTS: Conditional gene knockout strategy combined with histology and whole-transcriptomic analysis showed that Tsc2 deficiency in macrophages aggravated the progression of aortic aneurysms along with an upregulation of proinflammatory cytokines and matrix metallopeptidase-9 in the angiotensin II-induced mouse model. G protein-coupled receptor 68 (Gpr68), a proton-sensing receptor for detecting the extracellular acidic pH, was identified as the most up-regulated gene in Tsc2 deficient macrophages compared with control macrophages. Additionally, Tsc2 deficient macrophages displayed higher glycolysis and glycolytic inhibitor 2-deoxy-D-glucose treatment partially attenuated the level of Gpr68. We further demonstrated an Tsc2-Gpr68-CREB network in macrophages that regulates the inflammatory response, proteolytic degradation and vascular homeostasis. Gpr68 inhibition largely abrogated the progression of aortic aneurysms caused by Tsc2 deficiency in macrophages.
CONCLUSIONS: The findings reveal that Tsc2 deficiency in macrophages contributes to aortic aneurysm formation, at least in part, by upregulating Gpr68 expression, which subsequently drives proinflammatory processes and matrix metallopeptidase activation. The data also provide a novel therapeutic strategy to limit the progression of the aneurysm resulting from Tsc2 mutations.

DOI: https://doi.org/10.1038/s41419-022-05423-2

Eur J Neurosci. 2022 Nov 15.

Developmental dynamics of the impact of constitutive mTORC1 hyperactivity and environmental enrichment on structural synaptic plasticity and behaviour in a rat model of autism spectrum disorder.

Simon Granak, Klara Tuckova, Viera Kutna, Iveta Vojtechova, Laura Bajkova, Tomas Petrasek, Saak V Ovsepian.

Autism spectrum disorder (ASD) is a neurodevelopmental condition causing a range of social and communication impairments. Although the role of multiple genes and environmental factors has been reported, the impact of the interplay between genes and environment on the onset and progression of the disease remains elusive. We housed wild-type (Tsc2+/+) and tuberous sclerosis 2 deficient (Tsc2+/-) Eker rats (ASD model) in individually ventilated cages or enriched conditions and conducted a series of behavioural tests followed by the histochemical analysis of dendritic spines and plasticity in three age groups (days 45, 90, and 365). The elevated plus-maze test revealed a reduction of anxiety by enrichment, while the mobility of young and adult Eker rats in the open field was lower compared to wild-type. In the social interaction test, an enriched environment reduced social contact in the youngest group and increased anogenital exploration in 90- and 365-day-old rats. Self-grooming was increased by environmental enrichment in young and adult rats and decreased in aged Eker rats. Dendritic spine counts revealed an increased spine density in the cingulate gyrus in adult Ekers irrespective of housing conditions, whereas spine density in hippocampal pyramidal neurons was comparable across all genotypes and groups. Morphometric analysis of dendritic spines revealed age-related changes in spine morphology and density which were responsive to animal genotype and environment. Taken together, our findings suggest that under TSC2 haploinsufficiency and mTORC1 hyperactivity, the expression of behavioural signs and neuroplasticity in Eker rats can be differentially influenced by the developmental stage and environment.

Keywords: Eker rats; animal models of autism; cingulate gyrus; enriched environment; open field test; tuberous sclerosis complex, dendritic spine

DOI: https://doi.org/10.1111/ejn.15864