Towards a better understanding of the neuro-developmental role of autophagy in sickness and in health

Autophagy is a critical cellular process by which biomolecules and cellular organelles are degraded in an orderly manner inside lysosomes. This process is particularly important in neurons: these post-mitotic cells cannot divide or be easily replaced and are therefore especially sensitive to the accumulation of toxic proteins and damaged organelles. Dysregulation of neuronal autophagy is well documented in a range of neurodegenerative diseases. However, growing evidence indicates that autophagy also critically contributes to neurodevelopmental cellular processes, including neurogenesis, maintenance of neural stem cell homeostasis, differentiation, metabolic reprogramming, and synaptic remodelling. These findings implicate autophagy in neurodevelopmental disorders. In this review we discuss the current understanding of the role of autophagy in neurodevelopment and neurodevelopmental disorders, as well as currently available tools and techniques that can be used to further investigate this association.

Download Full-text

Repression of differentiation genes by Hes transcription factors fuels neural tumour growth in Drosophila

The International Journal of Developmental Biology ◽

10.1387/ijdb.210187cd ◽

2021 ◽

Author(s):

Chrysanthi Voutyraki ◽

Alexandros Choromidis ◽

Vasiliki Theodorou ◽

Christina Efraimoglou ◽

Gerasimos Anagnostopoulos ◽

...

Keyword(s):

Stem Cell ◽

Transcription Factors ◽

Notch Signaling ◽

Tumour Growth ◽

Metabolic Reprogramming ◽

Cell Physiology ◽

Malignant Tumours ◽

Rna Profiling ◽

A Cell

Background: Neural stem cells (NSC) in divide asymmetrically to generate a cell that retains stem cell identity and another that is routed to differentiation. Prolonged mitotic activity of the NSCs gives rise to the plethora of neurons and glial cells that wire the brain and nerve cord. Genetic insults, such as excess of Notch signaling, perturb the normal NSC proliferation programs and trigger the formation of NSC hyperplasias, that can later progress to malignancies. Hes proteins are crucial mediators of Notch signaling and in the NSC context they act by repressing a cohort of early pro-differentiation transcription factors. Downregulation of these pro-differentiation factors makes NSC progeny cells susceptible to adopting an aberrant stem cell program. We have recently shown that Hes overexpression in Drosophila leads to NSC hyperplasias that progress to malignant tumours after allografting to adult hosts. Methods: We have combined genetic analysis, tissue allografting and transcriptomic approaches to address the role of Hes genes in NSC malignant transformation. Results: We show that the E(spl) genes are important mediators in the progression of Notch hyperplasias to malignancy, since allografts lacking the E(spl) genes grow much slower. We further present RNA profiling of Hes-induced tumours at two different stages after allografting. We find that the same cohort of differentiation-promoting transcription factors that are repressed in the primary hyperplasias continue to be downregulated after transplantation. This is accompanied by an upregulation of stress-response genes and metabolic reprogramming. Conclusions: The combination of dedifferentiation and cell physiology changes most likely drive tumour growth.

Download Full-text

Advances in the role of m6A RNA modification in cancer metabolic reprogramming

Cell & Bioscience ◽

10.1186/s13578-020-00479-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Xiu Han ◽

Lin Wang ◽

Qingzhen Han

Keyword(s):

Cancer Cells ◽

Epigenetic Modification ◽

Metabolic Reprogramming ◽

Regulatory Mechanisms ◽

Rna Modification ◽

Biological Functions ◽

Rna Transcription ◽

Cellular Processes ◽

Metabolic Genes

Abstract N6-methyladenosine (m6A) modification is the most common internal modification of eukaryotic mRNA and is widely involved in many cellular processes, such as RNA transcription, splicing, nuclear transport, degradation, and translation. m6A has been shown to plays important roles in the initiation and progression of various cancers. The altered metabolic programming of cancer cells promotes their cell-autonomous proliferation and survival, leading to an indispensable hallmark of cancers. Accumulating evidence has demonstrated that this epigenetic modification exerts extensive effects on the cancer metabolic network by either directly regulating the expression of metabolic genes or modulating metabolism-associated signaling pathways. In this review, we summarized the regulatory mechanisms and biological functions of m6A and its role in cancer metabolic reprogramming.

Download Full-text

The Contribution of Autophagy and LncRNAs to MYC-Driven Gene Regulatory Networks in Cancers

International Journal of Molecular Sciences ◽

10.3390/ijms22168527 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8527

Author(s):

Leila Jahangiri ◽

Perla Pucci ◽

Tala Ishola ◽

Ricky M. Trigg ◽

John A. Williams ◽

...

Keyword(s):

Gene Networks ◽

Regulatory Networks ◽

Metabolic Reprogramming ◽

Cellular Processes ◽

Cancer Genomes ◽

Mutual Regulation ◽

Myc Gene ◽

Gene Regulatory ◽

Non Coding Rnas

MYC is a target of the Wnt signalling pathway and governs numerous cellular and developmental programmes hijacked in cancers. The amplification of MYC is a frequently occurring genetic alteration in cancer genomes, and this transcription factor is implicated in metabolic reprogramming, cell death, and angiogenesis in cancers. In this review, we analyse MYC gene networks in solid cancers. We investigate the interaction of MYC with long non-coding RNAs (lncRNAs). Furthermore, we investigate the role of MYC regulatory networks in inducing changes to cellular processes, including autophagy and mitophagy. Finally, we review the interaction and mutual regulation between MYC and lncRNAs, and autophagic processes and analyse these networks as unexplored areas of targeting and manipulation for therapeutic gain in MYC-driven malignancies.

Download Full-text

Chemoresistance, Cancer Stem Cells, and miRNA Influences: The Case for Neuroblastoma

Analytical Cellular Pathology ◽

10.1155/2015/150634 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8 ◽

Cited By ~ 18

Author(s):

Alfred Buhagiar ◽

Duncan Ayers

Keyword(s):

Stem Cell ◽

Basic Research ◽

Sympathetic Ganglia ◽

The Body ◽

Nerve Tissue ◽

Diagnostic Tools ◽

Stem Cell Maintenance ◽

Cellular Processes ◽

Cellular Pathways

Neuroblastoma is a type of cancer that develops most often in infants and children under the age of five years. Neuroblastoma originates within the peripheral sympathetic ganglia, with 30% of the cases developing within the adrenal medulla, although it can also occur within other regions of the body such as nerve tissue in the spinal cord, neck, chest, abdomen, and pelvis. MicroRNAs (miRNAs) regulate cellular pathways, differentiation, apoptosis, and stem cell maintenance. Such miRNAs regulate genes involved in cellular processes. Consequently, they are implicated in the regulation of a spectrum of signaling pathways within the cell. In essence, the role of miRNAs in the development of cancer is of utmost importance for the understanding of dysfunctional cellular pathways that lead to the conversion of normal cells into cancer cells. This review focuses on highlighting the recent, important implications of miRNAs within the context of neuroblastoma basic research efforts, particularly concerning miRNA influences on cancer stem cell pathology and chemoresistance pathology for this condition, together with development of translational medicine approaches for novel diagnostic tools and therapies for this neuroblastoma.

Download Full-text

The role of translationally controlled tumor protein in proliferation ofDrosophilaintestinal stem cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1910850116 ◽

2019 ◽

Vol 116 (52) ◽

pp. 26591-26598 ◽

Cited By ~ 2

Author(s):

Young V. Kwon ◽

Bingqing Zhao ◽

Chiwei Xu ◽

Jiae Lee ◽

Chiao-Lin Chen ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Signaling Pathways ◽

Hippo Pathway ◽

Tissue Homeostasis ◽

Translationally Controlled Tumor Protein ◽

Cellular Processes ◽

The Hippo Pathway

Translationally controlled tumor protein (TCTP) is a highly conserved protein functioning in multiple cellular processes, ranging from growth to immune responses. To explore the role of TCTP in tissue maintenance and regeneration, we employed the adultDrosophilamidgut, where multiple signaling pathways interact to precisely regulate stem cell division for tissue homeostasis. Tctp levels were significantly increased in stem cells and enteroblasts upon tissue damage or activation of the Hippo pathway that promotes regeneration of intestinal epithelium. Stem cells with reduced Tctp levels failed to proliferate during normal tissue homeostasis and regeneration. Mechanistically, Tctp forms a complex with multiple proteins involved in translation and genetically interacts with ribosomal subunits. In addition, Tctp increases both Akt1 protein abundance and phosphorylation in vivo. Altogether, Tctp regulates stem cell proliferation by interacting with key growth regulatory signaling pathways and the translation process in vivo.

Download Full-text

Role of miR-146a in neural stem cell differentiation and neural lineage determination: relevance for neurodevelopmental disorders

Molecular Autism ◽

10.1186/s13229-018-0219-3 ◽

2018 ◽

Vol 9 (1) ◽

Cited By ~ 18

Author(s):

Lam Son Nguyen ◽

Julien Fregeac ◽

Christine Bole-Feysot ◽

Nicolas Cagnard ◽

Anand Iyer ◽

...

Keyword(s):

Stem Cell ◽

Cell Differentiation ◽

Neural Stem Cell ◽

Neurodevelopmental Disorders ◽

Stem Cell Differentiation ◽

Neural Lineage

Download Full-text

Primary Cilia in Glial Cells: An Oasis in the Journey to Overcoming Neurodegenerative Diseases

Frontiers in Neuroscience ◽

10.3389/fnins.2021.736888 ◽

2021 ◽

Vol 15 ◽

Author(s):

Soo Mi Ki ◽

Hui Su Jeong ◽

Ji Eun Lee

Keyword(s):

Neurodegenerative Diseases ◽

Glial Cells ◽

Primary Cilia ◽

Regulatory Mechanisms ◽

Close Attention ◽

Cellular Processes ◽

Cilia Formation ◽

And Function ◽

Cellular Organelles

Many neurodegenerative diseases have been associated with defects in primary cilia, which are cellular organelles involved in diverse cellular processes and homeostasis. Several types of glial cells in both the central and peripheral nervous systems not only support the development and function of neurons but also play significant roles in the mechanisms of neurological disease. Nevertheless, most studies have focused on investigating the role of primary cilia in neurons. Accordingly, the interest of recent studies has expanded to elucidate the role of primary cilia in glial cells. Correspondingly, several reports have added to the growing evidence that most glial cells have primary cilia and that impairment of cilia leads to neurodegenerative diseases. In this review, we aimed to understand the regulatory mechanisms of cilia formation and the disease-related functions of cilia, which are common or specific to each glial cell. Moreover, we have paid close attention to the signal transduction and pathological mechanisms mediated by glia cilia in representative neurodegenerative diseases. Finally, we expect that this field of research will clarify the mechanisms involved in the formation and function of glial cilia to provide novel insights and ideas for the treatment of neurodegenerative diseases in the future.

Download Full-text

Amino Acid Metabolic Vulnerabilities in Acute and Chronic Myeloid Leukemias

Frontiers in Oncology ◽

10.3389/fonc.2021.694526 ◽

2021 ◽

Vol 11 ◽

Author(s):

Aboli Bhingarkar ◽

Hima V. Vangapandu ◽

Sanjay Rathod ◽

Keito Hoshitsuki ◽

Christian A. Fernandez

Keyword(s):

Amino Acid ◽

Energy Demand ◽

Mammalian Target Of Rapamycin ◽

Metabolic Reprogramming ◽

General Control ◽

Comprehensive Overview ◽

Pyrimidine Synthesis ◽

Cellular Processes ◽

Myeloid Leukemias

Amino acid (AA) metabolism plays an important role in many cellular processes including energy production, immune function, and purine and pyrimidine synthesis. Cancer cells therefore require increased AA uptake and undergo metabolic reprogramming to satisfy the energy demand associated with their rapid proliferation. Like many other cancers, myeloid leukemias are vulnerable to specific therapeutic strategies targeting metabolic dependencies. Herein, our review provides a comprehensive overview and TCGA data analysis of biosynthetic enzymes required for non-essential AA synthesis and their dysregulation in myeloid leukemias. Furthermore, we discuss the role of the general control nonderepressible 2 (GCN2) and-mammalian target of rapamycin (mTOR) pathways of AA sensing on metabolic vulnerability and drug resistance.

Download Full-text