Autophagy deficiency in neurodevelopmental disorders

AbstractAutophagy is a cell self-digestion pathway through lysosome and plays a critical role in maintaining cellular homeostasis and cytoprotection. Characterization of autophagy related genes in cell and animal models reveals diverse physiological functions of autophagy in various cell types and tissues. In central nervous system, by recycling injured organelles and misfolded protein complexes or aggregates, autophagy is integrated into synaptic functions of neurons and subjected to distinct regulation in presynaptic and postsynaptic neuronal compartments. A plethora of studies have shown the neuroprotective function of autophagy in major neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS). Recent human genetic and genomic evidence has demonstrated an emerging, significant role of autophagy in human brain development and prevention of spectrum of neurodevelopmental disorders. Here we will review the evidence demonstrating the causal link of autophagy deficiency to congenital brain diseases, the mechanism whereby autophagy functions in neurodevelopment, and therapeutic potential of autophagy.

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Myotubularin-related phosphatase 5 is a critical determinant of autophagy in neurons

10.1101/2021.07.20.453106 ◽

2021 ◽

Author(s):

Jason P. Chua ◽

Karan Bedi ◽

Michelle T. Paulsen ◽

Mats Ljungman ◽

Elizabeth M.H. Tank ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Therapeutic Potential ◽

Cell Types ◽

Live Cells ◽

Nascent Transcript ◽

Critical Determinant ◽

Autophagy Induction ◽

A Cell ◽

Lysosome Degradation ◽

Induced Pluripotent

Autophagy is a conserved, multi-step process of capturing proteolytic cargo in autophagosomes for lysosome degradation. The capacity to remove toxic proteins that accumulate in neurodegenerative disorders attests to the disease-modifying potential of the autophagy pathway. However, neurons respond only marginally to conventional methods for inducing autophagy, limiting efforts to develop therapeutic autophagy modulators for neurodegenerative diseases. The determinants underlying poor autophagy induction in neurons and the degree to which neurons and other cell types are differentially sensitive to autophagy stimuli are incompletely defined. Accordingly, we sampled nascent transcript synthesis and stabilities in fibroblasts, induced pluripotent stem cells (iPSCs) and iPSC-derived neurons (iNeurons), thereby uncovering a neuron-specific stability of transcripts encoding myotubularin-related phosphatase 5 (MTMR5). MTMR5 is an autophagy suppressor that acts with its binding partner, MTMR2, to dephosphorylate phosphoinositides critical for autophagy initiation and autophagosome maturation. We found that MTMR5 is necessary and sufficient to suppress autophagy in iNeurons and undifferentiated iPSCs. Using optical pulse labeling to visualize the turnover of endogenously-encoded proteins in live cells, we observed that knockdown of MTMR5 or MTMR2, but not MTMR9, significantly enhances neuronal degradation of TDP-43, an autophagy substrate implicated in several neurodegenerative diseases. Accordingly, our findings establish a regulatory mechanism of autophagy intrinsic to neurons and targetable for clearing disease-related proteins in a cell type-specific manner. In so doing, our results not only unravel novel aspects of neuronal biology and proteostasis, but also elucidate a strategy for modulating neuronal autophagy that could be of high therapeutic potential for multiple neurodegenerative diseases.

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Expression weighted cell type enrichments reveal genetic and cellular nature of major brain disorders

10.1101/032680 ◽

2015 ◽

Author(s):

Nathan G. Skene ◽

Seth G.N. Grant

Keyword(s):

Multiple Sclerosis ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cell Types ◽

Brain Diseases ◽

Causative Mutation ◽

Specific Marker ◽

Brain Disorders ◽

Cell Type ◽

A Cell

AbstractThe cell types that trigger the primary pathology in many brain diseases remain largely unknown. One route to understanding the primary pathological cell type for a particular disease is to identify the cells expressing susceptibility genes. Although this is straightforward for monogenic conditions where the causative mutation may alter expression of a cell type specific marker, methods are required for the common polygenic disorders. We developed the Expression Weighted Cell Type Enrichment (EWCE) method that uses single cell transcriptomes to generate the probability distribution associated with a gene list having an average level of expression within a cell type. Following validation, we applied EWCE to human genetic data from cases of epilepsy, Schizophrenia, Autism, Intellectual Disability, Alzheimer’s disease, Multiple Sclerosis and anxiety disorders. Genetic susceptibility primarily affected microglia in Alzheimer’s and Multiple Sclerosis; was shared between interneurons and pyramidal neurons in Autism and Schizophrenia; while intellectual disabilities and epilepsy were attributable to a range of cell-types, with the strongest enrichment in interneurons. We hypothesized that the primary cell type pathology could trigger secondary changes in other cell types and these could be detected by applying EWCE to transcriptome data from diseased tissue. In Autism, Schizophrenia and Alzheimer’s disease we find evidence of pathological changes in all of the major brain cell types. These findings give novel insight into the cellular origins and progression in common brain disorders. The methods can be applied to any tissue and disorder and have applications in validating mouse models.

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Presence and distribution of specific prosome antigens change as a function of embryonic development and tissue-type differentiation in Pleurodeles waltl

Journal of Cell Science ◽

10.1242/jcs.90.4.555 ◽

1988 ◽

Vol 90 (4) ◽

pp. 555-567 ◽

Cited By ~ 3

Author(s):

J.K. Pal ◽

P. Gounon ◽

M.F. Grossi de Sa ◽

K. Scherrer

Keyword(s):

Protein Complexes ◽

Cell Types ◽

Immunoblot Analysis ◽

Tissue Type ◽

Animal Pole ◽

Development And Differentiation ◽

A Cell ◽

Pleurodeles Waltl ◽

Rna Protein Complexes ◽

Swimming Larva

The prosomes, biochemically well characterized small RNA-protein complexes, found associated with mRNA in all eukaryotic cells tested, have been identified as maternal components in sea urchin and chick embryos. In this study, we investigated their presence and cytolocalization in the oocytes and embryos of Pleurodeles waltl by immunoblot analysis and immunofluorescence, using monoclonal antibodies prepared against duck prosome proteins. Of the four antibodies tested, three recognized the corresponding antigens in oocyte total protein extracts. Immunofluorescence analysis, using the three prosomal antibodies, demonstrated a drastic change in the localization of the prosome antigens, which changed from the cytoplasm to the nucleus during oogenesis. In the nucleus, in diplotene stages, prosomal antigens appeared to be associated with the lampbrush chromosomes and the nuclear matrix. During embryogenesis, the subcellular distribution of the prosome antigens was a function of development and differentiation: in the cleavage stages up to the mid-blastula they were localized in the cytoplasm and on the plasma membrane, while in the late blastula, gastrula and neurula they were in the nucleus. Interestingly, one of the prosome antigens, p31K, was found to be in a different location in certain cells in the animal pole of the mid-blastula and was absent in the neural tissue in the neurula. In still later stages, in the free-swimming larva, all three antigens were localized in the cytoplasm, specifically in certain cell types in the epidermal tissues. Furthermore, they were sectorially distributed in the cytoplasm. These data taken together indicate the possible presence of tissue-type-specific prosome antigens in Pleurodeles. Differentiation-dependent subcellular localization of the prosome antigens suggests a cell-compartment-related multiple function of prosomes.

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Development and Characterization of Human Cerebral Organoids

Cell Transplantation ◽

10.1177/0963689717752946 ◽

2018 ◽

Vol 27 (3) ◽

pp. 393-406 ◽

Cited By ~ 14

Author(s):

Abraam M. Yakoub ◽

Mark Sadek

Keyword(s):

Stem Cell ◽

Neurodevelopmental Disorders ◽

Therapeutic Potential ◽

Cell Types ◽

3 Dimensional ◽

Brain Functions ◽

Optimized Protocol ◽

The Cost ◽

Necessary And Sufficient

Studies of human neurodevelopmental disorders and stem cell–based regenerative transplants have been hampered by the lack of a model of the developing human brain. Stem cell–derived neurons suffer major limitations, including the ability to recapitulate the 3-dimensional architecture of a brain tissue and the representation of multiple layers and cell types that contribute to the overall brain functions in vivo. Recently, cerebral organoid technology was introduced; however, such technology is still in its infancy, and its low reproducibility and limitations significantly reduce the reliability of such a model as it currently exists, especially considering the complexity of cerebral-organoid protocols. Here we have tested and compared multiple protocols and conditions for growth of organoids, and we describe an optimized methodology, and define the necessary and sufficient factors that support the development of optimal organoids. Our optimization criteria included organoids’ overall growth and size, stratification and representation of the various cell types, inter-batch variability, analysis of neuronal maturation, and even the cost of the procedure. Importantly, this protocol encompasses a plethora of technical tips that allow researchers to easily reproduce it and obtain reliable organoids with the least variability, and showcases a robust array of approaches to characterize successful organoids. This optimized protocol provides a reliable system for genetic or pharmacological (drug development) screens and may enhance understanding and therapy of human neurodevelopmental disorders, including harnessing the therapeutic potential of stem cell–derived transplants.

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Role of claudin species–specific dynamics in reconstitution and remodeling of the zonula occludens

Molecular Biology of the Cell ◽

10.1091/mbc.e10-12-1003 ◽

2011 ◽

Vol 22 (9) ◽

pp. 1495-1504 ◽

Cited By ~ 35

Author(s):

Yuji Yamazaki ◽

Reitaro Tokumasu ◽

Hiroshi Kimura ◽

Sachiko Tsukita

Keyword(s):

Epithelial Cells ◽

Critical Role ◽

Freeze Fracture ◽

Cell Types ◽

Cell System ◽

Loosely Coupled ◽

Zonula Occludens ◽

A Cell ◽

Recovery Dynamics ◽

Species Specific

Tight-junction strands, which are organized into the beltlike cell–cell adhesive structure called the zonula occludens (TJ), create the paracellular permselective barrier in epithelial cells. The TJ is constructed on the basis of the zonula adherens (AJ) by polymerized claudins in a process mediated by ZO-1/2, but whether the 24 individual claudin family members play different roles at the TJ is unclear. Here we established a cell system for examining the polymerization of individual claudins in the presence of ZO-1/2 using an epithelial-like cell line, SF7, which lacked endogenous TJs and expressed no claudin but claudin-12 in immunofluorescence and real-time PCR assays. In stable SF7-derived lines, exogenous claudin-7, -14, or -19, but no other claudins, individually reconstituted TJs, each with a distinct TJ-strand pattern, as revealed by freeze-fracture analyses. Fluorescence recovery after photobleaching (FRAP) analyses of the claudin dynamics in these and other epithelial cells suggested that slow FRAP-recovery dynamics of claudins play a critical role in regulating their polymerization around AJs, which are loosely coupled with ZO-1/2, to form TJs. Furthermore, the distinct claudin stabilities in different cell types may help to understand how TJs regulate paracellular permeability by altering the paracellular flux and the paracellular ion permeability.

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The Effect and Regulatory Mechanism of High Mobility Group Box-1 Protein on Immune Cells in Inflammatory Diseases

Cells ◽

10.3390/cells10051044 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1044

Author(s):

Yun Ge ◽

Man Huang ◽

Yong-ming Yao

Keyword(s):

Immune Cells ◽

Molecular Mechanisms ◽

Immune Cell ◽

Therapeutic Potential ◽

Inflammatory Diseases ◽

Critical Role ◽

High Mobility ◽

Cell Types ◽

High Mobility Group ◽

High Mobility Group Protein

High mobility group box-1 protein (HMGB1), a member of the high mobility group protein superfamily, is an abundant and ubiquitously expressed nuclear protein. Intracellular HMGB1 is released by immune and necrotic cells and secreted HMGB1 activates a range of immune cells, contributing to the excessive release of inflammatory cytokines and promoting processes such as cell migration and adhesion. Moreover, HMGB1 is a typical damage-associated molecular pattern molecule that participates in various inflammatory and immune responses. In these ways, it plays a critical role in the pathophysiology of inflammatory diseases. Herein, we review the effects of HMGB1 on various immune cell types and describe the molecular mechanisms by which it contributes to the development of inflammatory disorders. Finally, we address the therapeutic potential of targeting HMGB1.

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MicroRNA regulation of BAG3

Experimental Biology and Medicine ◽

10.1177/15353702211066908 ◽

2022 ◽

pp. 153537022110669

Author(s):

Madhu V Singh ◽

Karthik Dhanabalan ◽

Joseph Verry ◽

Ayotunde O Dokun

Keyword(s):

Critical Role ◽

B Cell Lymphoma ◽

Cell Types ◽

Biological Processes ◽

Adaptive Responses ◽

Protein Coding ◽

Microrna Regulation ◽

A Cell ◽

Artery Disease

B-cell lymphoma 2 (Bcl-2)-associated athanogene 3 (BAG3) protein is a member of BAG family of co-chaperones that modulates major biological processes, including apoptosis, autophagy, and development to promote cellular adaptive responses to stress stimuli. Although BAG3 is constitutively expressed in several cell types, its expression is also inducible and is regulated by microRNAs (miRNAs). miRNAs are small non-coding RNAs that mostly bind to the 3′-UTR (untranslated region) of mRNAs to inhibit their translation or to promote their degradation. miRNAs can potentially regulate over 50% of the protein-coding genes in a cell and therefore are involved in the regulation of all major functions, including cell differentiation, growth, proliferation, apoptosis, and autophagy. Dysregulation of miRNA expression is associated with pathogenesis of numerous diseases, including peripheral artery disease (PAD). BAG3 plays a critical role in regulating the response of skeletal muscle cells to ischemia by its ability to regulate autophagy. However, the biological role of miRNAs in the regulation of BAG3 in biological processes has only been elucidated recently. In this review, we discuss how miRNA may play a key role in regulating BAG3 expression under normal and pathological conditions.

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Diagnostic and Therapeutic Potential of TSPO Studies Regarding Neurodegenerative Diseases, Psychiatric Disorders, Alcohol Use Disorders, Traumatic Brain Injury, and Stroke: An Update

Cells ◽

10.3390/cells9040870 ◽

2020 ◽

Vol 9 (4) ◽

pp. 870 ◽

Cited By ~ 4

Author(s):

Jasmina Dimitrova-Shumkovska ◽

Ljupcho Krstanoski ◽

Leo Veenman

Keyword(s):

Cell Death ◽

Brain Injury ◽

Therapeutic Potential ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Cell Types ◽

Translocator Protein ◽

Brain Diseases ◽

Positron Emission ◽

The Brain

Neuroinflammation and cell death are among the common symptoms of many central nervous system diseases and injuries. Neuroinflammation and programmed cell death of the various cell types in the brain appear to be part of these disorders, and characteristic for each cell type, including neurons and glia cells. Concerning the effects of 18-kDa translocator protein (TSPO) on glial activation, as well as being associated with neuronal cell death, as a response mechanism to oxidative stress, the changes of its expression assayed with the aid of TSPO-specific positron emission tomography (PET) tracers’ uptake could also offer evidence for following the pathogenesis of these disorders. This could potentially increase the number of diagnostic tests to accurately establish the stadium and development of the disease in question. Nonetheless, the differences in results regarding TSPO PET signals of first and second generations of tracers measured in patients with neurological disorders versus healthy controls indicate that we still have to understand more regarding TSPO characteristics. Expanding on investigations regarding the neuroprotective and healing effects of TSPO ligands could also contribute to a better understanding of the therapeutic potential of TSPO activity for brain damage due to brain injury and disease. Studies so far have directed attention to the effects on neurons and glia, and processes, such as death, inflammation, and regeneration. It is definitely worthwhile to drive such studies forward. From recent research it also appears that TSPO ligands, such as PK11195, Etifoxine, Emapunil, and 2-Cl-MGV-1, demonstrate the potential of targeting TSPO for treatments of brain diseases and disorders.

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Interferon Lambda in the Pathogenesis of Inflammatory Bowel Diseases

Frontiers in Immunology ◽

10.3389/fimmu.2021.767505 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jonathan W. Wallace ◽

David A. Constant ◽

Timothy J. Nice

Keyword(s):

Inflammatory Bowel Disease ◽

Epithelial Cell ◽

Epithelial Cells ◽

Bowel Disease ◽

Therapeutic Potential ◽

Critical Role ◽

Cell Types ◽

Receptor Expression ◽

Bowel Diseases ◽

Inflammatory Bowel

Interferon λ (IFN-λ) is critical for host viral defense at mucosal surfaces and stimulates immunomodulatory signals, acting on epithelial cells and few other cell types due to restricted IFN-λ receptor expression. Epithelial cells of the intestine play a critical role in the pathogenesis of Inflammatory Bowel Disease (IBD), and the related type II interferons (IFN-γ) have been extensively studied in the context of IBD. However, a role for IFN-λ in IBD onset and progression remains unclear. Recent investigations of IFN-λ in IBD are beginning to uncover complex and sometimes opposing actions, including pro-healing roles in colonic epithelial tissues and potentiation of epithelial cell death in the small intestine. Additionally, IFN-λ has been shown to act through non-epithelial cell types, such as neutrophils, to protect against excessive inflammation. In most cases IFN-λ demonstrates an ability to coordinate the host antiviral response without inducing collateral hyperinflammation, suggesting that IFN-λ signaling pathways could be a therapeutic target in IBD. This mini review discusses existing data on the role of IFN-λ in the pathogenesis of inflammatory bowel disease, current gaps in the research, and therapeutic potential of modulating the IFN-λ-stimulated response.

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Alteration of STIM1/Orai1-Mediated SOCE in Skeletal Muscle: Impact in Genetic Muscle Diseases and Beyond

Cells ◽

10.3390/cells10102722 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2722

Author(s):

Elena Conte ◽

Paola Imbrici ◽

Paola Mantuano ◽

Maria Coppola ◽

Giulia Maria Camerino ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Function ◽

Molecular Mechanisms ◽

Therapeutic Potential ◽

Critical Role ◽

Protein A ◽

Cell Types ◽

Muscle Diseases ◽

Cellular Processes ◽

And Function

Intracellular Ca2+ ions represent a signaling mediator that plays a critical role in regulating different muscular cellular processes. Ca2+ homeostasis preservation is essential for maintaining skeletal muscle structure and function. Store-operated Ca2+ entry (SOCE), a Ca2+-entry process activated by depletion of intracellular stores contributing to the regulation of various function in many cell types, is pivotal to ensure a proper Ca2+ homeostasis in muscle fibers. It is coordinated by STIM1, the main Ca2+ sensor located in the sarcoplasmic reticulum, and ORAI1 protein, a Ca2+-permeable channel located on transverse tubules. It is commonly accepted that Ca2+ entry via SOCE has the crucial role in short- and long-term muscle function, regulating and adapting many cellular processes including muscle contractility, postnatal development, myofiber phenotype and plasticity. Lack or mutations of STIM1 and/or Orai1 and the consequent SOCE alteration have been associated with serious consequences for muscle function. Importantly, evidence suggests that SOCE alteration can trigger a change of intracellular Ca2+ signaling in skeletal muscle, participating in the pathogenesis of different progressive muscle diseases such as tubular aggregate myopathy, muscular dystrophy, cachexia, and sarcopenia. This review provides a brief overview of the molecular mechanisms underlying STIM1/Orai1-dependent SOCE in skeletal muscle, focusing on how SOCE alteration could contribute to skeletal muscle wasting disorders and on how SOCE components could represent pharmacological targets with high therapeutic potential.

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