Autophagy in Neurodevelopmental Disorders

Lv, Meihong

doi:10.1007/978-981-15-4272-5_11

Cited by 6 publications

(4 citation statements)

References 72 publications

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“…Among these eight nodes, we found variants in MTOR (c.2805G>A, PHRED = 18.86) and RICTOR (c.5084C>T, PHRED = 13.60) genes. These findings support the role of autophagy in neurodevelopmental diseases ( Marsh and Dragich, 2019 ; Lv et al, 2020 ) with a specific reference to mTORopathies ( Karalis and Bateup, 2021 ) that lead to epilepsy, ASD and, present in this patient, intellectual disability, obesity and hyperphagia. Worthy of note, NDE1 was included in the top50 genes ranked by betweenness centrality, highlighting its role in the network topology.…”

Section: Discussionsupporting

confidence: 83%

Whole Exome Sequencing in 16p13.11 Microdeletion Patients Reveals New Variants Through Deductive and Systems Medicine Approaches

et al. 2022

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The 16p13.11 microdeletion, whose prevalence in the general population is about 0.04%, is known in literature as a predisposition factor to neurodevelopmental disorders, being found in about 0.13% of patients with schizophrenia, in 0.5–0.6% of patient with epilepsy, cognitive impairment, autism spectrum disorder (ASD) and aggressiveness. The goal of this study was to identify a specific gene set pattern unique for the affected patients in comparison with other familial components. Due to the incomplete penetrance of this copy number variant (CNV), we studied by whole exome sequencing (WES), with particular regard of 850 SFARI genes, three families with an affected member carrier of inherited 16p13.11 and 16p13.11p12.3 microdeletion and one family with an affected member with a de novo 16p13.11 microdeletion. By combining a deductive approach together with personalized network models, we identified gene signatures potentially capable of explaining the clinical phenotype. Candidate variants in genes of interest were identified as possibly involved in determining the neurological phenotype of the four patients, such as compound heterozygosity in CECR2, variants in MTOR and RICTOR genes, compound heterozygous single nucleotide variants in the LRRK2 gene. Moreover, genes present in the microdeletion region were partially present as central nodes, with a focus on NDE1. No additional pathogenetic or uncertain CNVs were found in all four patients. No significant variants were detected in genes included in the microdeletion in patients 1, 2 and 3, excluding the finding of unmasked recessive variants. In conclusion, WES is a fundamental tool in the genetic investigation of patients having a predisposing variant, which is not sufficient to define the clinical phenotype. Moreover, the analysis of WES data using Systems medicine tools, such as personalized network models, led to the prioritization of genes on a high throughput scale and to discover variants in genes that were not prioritized at first.

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Section: Discussionsupporting

confidence: 83%

Whole Exome Sequencing in 16p13.11 Microdeletion Patients Reveals New Variants Through Deductive and Systems Medicine Approaches

et al. 2022

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“…Although the possible role of CMA in embryonic development has not been studied, alterations in macroautophagy have been associated with developmental abnormalities, such as neuronal migration, dendritic differentiation, and synapsis formation and pruning, which are often considered to be causes of autism spectrum disorder, tuberous sclerosis, and fragile X syndrome [91]. CMA and specific protein degradation may be essential processes in brain development.…”

Section: Induction Of Chaperone-mediated Autophagy (Cma) Activity In ...mentioning

confidence: 99%

Pericyte–Glioblastoma Cell Interaction: A Key Target to Prevent Glioblastoma Progression

Pombero

García-López

2023

Cells

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Multiple biological processes rely on direct intercellular interactions to regulate cell proliferation and migration in embryonic development and cancer processes. Tumor development and growth depends on close interactions between cancer cells and cells in the tumor microenvironment. During embryonic development, morphogenetic signals and direct cell contacts control cell proliferation, polarity, and morphogenesis. Cancer cells communicate with cells in the tumor niche through molecular signals and intercellular contacts, thereby modifying the vascular architecture and antitumor surveillance processes and consequently enabling tumor growth and survival. While looking for cell-to-cell signaling mechanisms that are common to both brain development and cancer progression, we have studied the infiltration process in glioblastoma multiforme (GBM), which is the most malignant primary brain tumor and with the worst prognosis. Cell-to-cell contacts, by means of filopodia-like structures, between GBM cells and brain pericytes (PCs) are necessary for adequate cell signaling during cancer infiltration; similarly, contacts between embryonic regions, via cytonemes, are required for embryo regionalization and development. This GBM–PC interaction provokes two important changes in the physiological function of these perivascular cells, namely, (i) vascular co-option with changes in cell contractility and vascular malformation, and (ii) changes in the PC transcriptome, modifying the microvesicles and protein secretome, which leads to the development of an immunosuppressive phenotype that promotes tumor immune tolerance. Moreover, the GTPase Cdc42 regulates cell polarity across organisms, from yeast to humans, playing a central role in GBM cell–PC interaction and maintaining vascular co-option. As such, a review of the molecular and cellular mechanisms underlying the development and maintenance of the physical interactions between cancer cells and PCs is of particular interest.

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“…As for the mechanism of action, previous studies carried out in MEF cells demonstrated that SAHA induces autophagy by activating the ULK1 complex, which is the most upstream component in the core autophagy pathway, and by suppressing the mammalian target of rapamycin (mTOR), which in turn inhibits autophagy induction [ 27 ] ( Figure 3 B). While the significance of autophagy in neurodegenerative diseases has been extensively investigated, we are only beginning to understand its functioning during the early stages of brain development [ 41 , 42 ]. Moreover, several studies have shown that perturbations affecting autophagy may cause NDDs.…”

Section: The Role Of Saha As a Neuroactive Compoundmentioning

confidence: 99%

Suberoylanilide Hydroxamic Acid (SAHA) Is a Driver Molecule of Neuroplasticity: Implication for Neurological Diseases

Verrillo,

Di Palma,

de Bellis

et al. 2023

Biomolecules

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Neuroplasticity is a crucial property of the central nervous system to change its activity in response to intrinsic or extrinsic stimuli. This is mainly achieved through the promotion of changes in the epigenome. One of the epi-drivers priming this process is suberoylanilide hydroxamic acid (SAHA or Vorinostat), a pan-histone deacetylase inhibitor that modulates and promotes neuroplasticity in healthy and disease conditions. Knowledge of the specific molecular changes induced by this epidrug is an important area of neuro-epigenetics for the identification of new compounds to treat cognition impairment and/or epilepsy. In this review, we summarize the findings obtained in cellular and animal models of various brain disorders, highlighting the multiple mechanisms activated by SAHA, such as improvement of memory, learning and behavior, and correction of faulty neuronal functioning. Supporting this evidence, in vitro and in vivo data underline how SAHA positively regulates the expression of neuronal genes and microtubule dynamics, induces neurite outgrowth and spine density, and enhances synaptic transmission and potentiation. In particular, we outline studies regarding neurodevelopmental disorders with pharmaco-resistant seizures and/or severe cognitive impairment that to date lack effective drug treatments in which SAHA could ameliorate defective neuroplasticity.

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Autophagy in Neurodevelopmental Disorders

Cited by 6 publications

References 72 publications

Whole Exome Sequencing in 16p13.11 Microdeletion Patients Reveals New Variants Through Deductive and Systems Medicine Approaches

Whole Exome Sequencing in 16p13.11 Microdeletion Patients Reveals New Variants Through Deductive and Systems Medicine Approaches

Pericyte–Glioblastoma Cell Interaction: A Key Target to Prevent Glioblastoma Progression

Suberoylanilide Hydroxamic Acid (SAHA) Is a Driver Molecule of Neuroplasticity: Implication for Neurological Diseases

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