scholarly journals The Ncoa7 locus regulates V-ATPase formation and function, neurodevelopment and behaviour

2020 ◽  
Author(s):  
Enrico Castroflorio ◽  
Joery den Hoed ◽  
Daria Svistunova ◽  
Mattéa J. Finelli ◽  
Alberto Cebrian-Serrano ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Regulatory Protein ◽  
Molecular Function ◽  
Neuronal Connectivity ◽  
Nuclear Receptor Coactivator ◽  
Lysm Domain ◽  
Behavioural Assessment ◽  
And Function ◽  
The Brain

Abstract Members of the Tre2/Bub2/Cdc16 (TBC), lysin motif (LysM), domain catalytic (TLDc) protein family are associated with multiple neurodevelopmental disorders, although their exact roles in disease remain unclear. For example, nuclear receptor coactivator 7 (NCOA7) has been associated with autism, although almost nothing is known regarding the mode-of-action of this TLDc protein in the nervous system. Here we investigated the molecular function of NCOA7 in neurons and generated a novel mouse model to determine the consequences of deleting this locus in vivo. We show that NCOA7 interacts with the cytoplasmic domain of the vacuolar (V)-ATPase in the brain and demonstrate that this protein is required for normal assembly and activity of this critical proton pump. Neurons lacking Ncoa7 exhibit altered development alongside defective lysosomal formation and function; accordingly, Ncoa7 deletion animals exhibited abnormal neuronal patterning defects and a reduced expression of lysosomal markers. Furthermore, behavioural assessment revealed anxiety and social defects in mice lacking Ncoa7. In summary, we demonstrate that NCOA7 is an important V-ATPase regulatory protein in the brain, modulating lysosomal function, neuronal connectivity and behaviour; thus our study reveals a molecular mechanism controlling endolysosomal homeostasis that is essential for neurodevelopment. Graphic abstract

scholarly journals DJ-1 regulates the integrity and function of ER-mitochondria association through interaction with IP3R3-Grp75-VDAC1

2019 ◽  
Vol 116 (50) ◽  
pp. 25322-25328 ◽  
Author(s):  
Yi Liu ◽  
Xiaopin Ma ◽  
Hisashi Fujioka ◽  
Jun Liu ◽  
Shengdi Chen ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Cellular Mechanism ◽  
Loss Of Function ◽  
Wild Type ◽  
Calcium Efflux ◽  
And Function ◽  
The Brain ◽  
Early Onset Parkinson’S Disease

Loss-of-function mutations in DJ-1 are associated with autosomal recessive early onset Parkinson’s disease (PD), yet the underlying pathogenic mechanism remains elusive. Here we demonstrate that DJ-1 localized to the mitochondria-associated membrane (MAM) both in vitro and in vivo. In fact, DJ-1 physically interacts with and is an essential component of the IP3R3-Grp75-VDAC1 complexes at MAM. Loss of DJ-1 disrupted the IP3R3-Grp75-VDAC1 complex and led to reduced endoplasmic reticulum (ER)-mitochondria association and disturbed function of MAM and mitochondria in vitro. These deficits could be rescued by wild-type DJ-1 but not by the familial PD-associated L166P mutant which had demonstrated reduced interaction with IP3R3-Grp75. Furthermore, DJ-1 ablation disturbed calcium efflux-induced IP3R3 degradation after carbachol treatment and caused IP3R3 accumulation at the MAM in vitro. Importantly, similar deficits in IP3R3-Grp75-VDAC1 complexes and MAM were found in the brain of DJ-1 knockout mice in vivo. The DJ-1 level was reduced in the substantia nigra of sporadic PD patients, which was associated with reduced IP3R3-DJ-1 interaction and ER-mitochondria association. Together, these findings offer insights into the cellular mechanism in the involvement of DJ-1 in the regulation of the integrity and calcium cross-talk between ER and mitochondria and suggests that impaired ER-mitochondria association could contribute to the pathogenesis of PD.

STEM-18. STROMAL EXTRACELLULAR VESICLES DRIVE GLIOMA STEM CELL REPROGRAMMING

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi24-vi25
Author(s):  
Lata Adnani ◽  
Brian Meehan ◽  
Jordan Kassouf ◽  
Cristiana Spinelli ◽  
Nadim Tawil ◽  
...  
Keyword(s):  
Molecular Subtype ◽  
Extracellular Vesicle ◽  
Host Cells ◽  
Tumour Mass ◽  
Membrane Structures ◽  
And Function ◽  
Rate Limiting ◽  
The Brain

Abstract Glioblastoma multiforme (GBM) represents the most frequent and lethal form of brain tumors originating from glioma stem cells (GSCs). GBM remains lethal because the rate limiting patho-mechanisms remain poorly understood. In this regard, few limitations involve the diversity 'between' cellular states and the molecular/cellular complexity 'within' the tumour mass. Using cell based- and mouse- models, we explored extracellular vesicle (EV) mediated interactions between cancer and stromal cells impacting phenotypes of GSCs as a function of their molecular subtype. EVs are spherical membrane structures that cells release to expel different molecular cargo (lipids, proteins, RNA, DNA), which can be transported across a distance in the brain and taken up by various ‘recipient’ cells resulting in reprogramming of the recipient cell's content and function. In vivo, GSCs altered their pattern of NOTCH signalling and molecular phenotype as a function of proximity to non-transformed host cells in the brain. In vitro stromal EVs altered GSC sphere forming capacity, proteome and expression of mesenchymal markers. Thus, EV mediated tumour-stromal interactions could represent a biological switch and a novel targeting point in the biology of GBM.

scholarly journals ERAP140, a Conserved Tissue-Specific Nuclear Receptor Coactivator

2002 ◽  
Vol 22 (10) ◽  
pp. 3358-3372 ◽  
Author(s):  
Wenlin Shao ◽  
Shlomit Halachmi ◽  
Myles Brown
Keyword(s):  
Nuclear Receptor ◽  
Target Genes ◽  
Tissue Type ◽  
Interacting Proteins ◽  
Nuclear Receptor Coactivator ◽  
Nuclear Receptor Coactivators ◽  
The Brain ◽  
Identification And Characterization

ABSTRACT We report here the identification and characterization of a novel nuclear receptor coactivator, ERAP140. ERAP140 was isolated in a screen for ERα-interacting proteins using the ERα ligand binding domain as a probe. The ERAP140 protein shares no sequence and has little structural homology with other nuclear receptor cofactors. However, homologues of ERAP140 have been identified in mouse, Drosophila, and Caenorhabditis elegans. The expression of ERAP140 is cell and tissue type specific and is most abundant in the brain, where its expression is restricted to neurons. In addition to interacting with ERα, ERAP140 also binds ERβ, TRβ, PPARγ, and RARα. ERAP140 interacts with ERα via a noncanonical interaction motif. The ERα-ERAP140 association can be competed by coactivator NR boxes, indicating ERAP140 binds ERα on a surface similar to that of other coactivators. ERAP140 can enhance the transcriptional activities of nuclear receptors with which it interacts. In vivo, ERAP140 is recruited by estrogen-bound ERα to the promoter region of endogenous ERα target genes. Furthermore, the E2-induced recruitment of ERAP140 to the promoter follows a cyclic pattern similar to that of other coactivators. Our results suggest that ERAP140 represents a distinct class of nuclear receptor coactivators that mediates receptor signaling in specific target tissues.

scholarly journals HAEMOLYMPH AND TISSUE TITRES OF ACHETAKININS IN THE HOUSE CRICKET ACHETA DOMESTICUS: EFFECT OF STARVATION AND DEHYDRATION

1994 ◽  
Vol 193 (1) ◽  
pp. 307-319 ◽  
Author(s):  
J Chung ◽  
G Goldsworthy ◽  
G Coast
Keyword(s):  
Acheta Domesticus ◽  
High Concentration ◽  
House Cricket ◽  
Immunoreactive Material ◽  
Access To Water ◽  
And Function ◽  
Thoracic And Abdominal ◽  
The Brain

Achetakinin-like immunoreactive material in tissues and haemolymph of adult male crickets was quantified by radioimmunoassay. Achetakinin-like material was found in the brain, suboesophageal ganglia and the thoracic and abdominal ganglia, but the largest amount was within the retrocerebral complex. A Ca2+-dependent release of achetakinin-like immunoreactive material was demonstrated from retrocerebral complexes incubated in vitro in saline containing a high concentration of K+. The concentration of achetakinin-like material in haemolymph from fed crickets was estimated to be 2.8 nmol l-1 and increased more than 10-fold in insects starved for 48 h without access to water. The presence of achetakinin-like material in haemolymph suggests that these peptides are released in vivo and function as circulating neurohormones.

scholarly journals Typical and atypical brain development: a review of neuroimaging studies

2013 ◽  
Vol 15 (3) ◽  
pp. 359-384 ◽  
Keyword(s):  
Brain Development ◽  
Neurodevelopmental Disorders ◽  
Fragile X ◽  
Early Adulthood ◽  
22Q11.2 Deletion Syndrome ◽  
Developmental Trajectory ◽  
Deletion Syndrome ◽  
Effective Interventions ◽  
And Function ◽  
The Brain

In the course of development, the brain undergoes a remarkable process of restructuring as it adapts to the environment and becomes more efficient in processing information. A variety of brain imaging methods can be used to probe how anatomy, connectivity, and function change in the developing brain. Here we review recent discoveries regarding these brain changes in both typically developing individuals and individuals with neurodevelopmental disorders. We begin with typical development, summarizing research on changes in regional brain volume and tissue density, cortical thickness, white matter integrity, and functional connectivity. Space limits preclude the coverage of all neurodevelopmental disorders; instead, we cover a representative selection of studies examining neural correlates of autism, attention deficit/hyperactivity disorder, Fragile X, 22q11.2 deletion syndrome, Williams syndrome, Down syndrome, and Turner syndrome. Where possible, we focus on studies that identify an age by diagnosis interaction, suggesting an altered developmental trajectory. The studies we review generally cover the developmental period from infancy to early adulthood. Great progress has been made over the last 20 years in mapping how the brain matures with MR technology. With ever-improving technology, we expect this progress to accelerate, offering a deeper understanding of brain development, and more effective interventions for neurodevelopmental disorders.

Amyloidosis

2010 ◽  
pp. 1766-1779
Author(s):  
M.B. Pepys ◽  
P.N. Hawkins
Keyword(s):  
Clinical Benefit ◽  
Clinical Condition ◽  
Amyloid Fibrils ◽  
Structure And Function ◽  
Seminal Vesicles ◽  
Amyloid Deposits ◽  
Precursor Proteins ◽  
And Function ◽  
The Brain

Amyloidosis is the clinical condition caused by extracellular deposition of amyloid in the tissues. Amyloid deposits are composed of amyloid fibrils, abnormal insoluble protein fibres formed by misfolding of their normally soluble precursors. About 30 different proteins can form clinically or pathologically significant amyloid fibrils in vivo as a result of either acquired or hereditary abnormalities. Small, focal, clinically silent amyloid deposits in the brain, heart, seminal vesicles, and joints are a universal accompaniment of ageing. However, clinically important amyloid deposits usually accumulate progressively, disrupting the structure and function of affected tissues and lead inexorably to organ failure and death. No treatment yet exists which can specifically clear amyloid deposits, but intervention which reduces the availability of the amyloid fibril precursor proteins may lead to amyloid regression with clinical benefit....

scholarly journals Human Somatostatin SST4 Receptor Transgenic Mice: Construction and Brain Expression Pattern Characterization

2021 ◽  
Vol 22 (7) ◽  
pp. 3758
Author(s):  
Balázs Nemes ◽  
Kata Bölcskei ◽  
Angéla Kecskés ◽  
Viktória Kormos ◽  
Balázs Gaszner ◽  
...  
Keyword(s):  
In Vivo Imaging ◽  
Regulatory Elements ◽  
Receptor Expression ◽  
Luciferase Reporter ◽  
Mouse Line ◽  
Humanized Mouse ◽  
Peripheral Tissues ◽  
And Function ◽  
The Brain

Somatostatin receptor subtype 4 (SST4) has been shown to mediate analgesic, antidepressant and anti-inflammatory functions without endocrine actions; therefore, it is proposed to be a novel target for drug development. To overcome the species differences of SST4 receptor expression and function between humans and mice, we generated an SST4 humanized mouse line to serve as a translational animal model for preclinical research. A transposon vector containing the hSSTR4 and reporter gene construct driven by the hSSTR4 regulatory elements were created. The vector was randomly inserted in Sstr4-deficient mice. hSSTR4 expression was detected by bioluminescent in vivo imaging of the luciferase reporter predominantly in the brain. RT-qPCR confirmed the expression of the human gene in the brain and various peripheral tissues consistent with the in vivo imaging. RNAscope in situ hybridization revealed the presence of hSSTR4 transcripts in glutamatergic excitatory neurons in the CA1 and CA2 regions of the hippocampus; in the GABAergic interneurons in the granular layer of the olfactory bulb and in both types of neurons in the primary somatosensory cortex, piriform cortex, prelimbic cortex and amygdala. This novel SST4 humanized mouse line might enable us to investigate the differences of human and mouse SST4 receptor expression and function and assess the effects of SST4 receptor agonist drug candidates.

scholarly journals l-Isoaspartyl Methyltransferase Deficiency in Zebrafish Leads to Impaired Calcium Signaling in the Brain

2021 ◽  
Vol 11 ◽  
Author(s):  
Remon Soliman ◽  
Maria Lorena Cordero-Maldonado ◽  
Teresa G. Martins ◽  
Mahsa Moein ◽  
Jean-François Conrotte ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Loss Of Function ◽  
Ht22 Cells ◽  
Homologous Genes ◽  
Vertebrate Model ◽  
And Function ◽  
First Time ◽  
The Brain ◽  
Isoaspartyl Methyltransferase

Isomerization of l-aspartyl and l-asparaginyl residues to l-isoaspartyl residues is one type of protein damage that can occur under physiological conditions and leads to conformational changes, loss of function, and enhanced protein degradation. Protein l-isoaspartyl methyltransferase (PCMT) is a repair enzyme whose action initiates the reconversion of abnormal l-isoaspartyl residues to normal l-aspartyl residues in proteins. Many lines of evidence support a crucial role for PCMT in the brain, but the mechanisms involved remain poorly understood. Here, we investigated PCMT activity and function in zebrafish, a vertebrate model that is particularly well-suited to analyze brain function using a variety of techniques. We characterized the expression products of the zebrafish PCMT homologous genes pcmt and pcmtl. Both zebrafish proteins showed a robust l-isoaspartyl methyltransferase activity and highest mRNA transcript levels were found in brain and testes. Zebrafish morphant larvae with a knockdown in both the pcmt and pcmtl genes showed pronounced morphological abnormalities, decreased survival, and increased isoaspartyl levels. Interestingly, we identified a profound perturbation of brain calcium homeostasis in these morphants. An abnormal calcium response upon ATP stimulation was also observed in mouse hippocampal HT22 cells knocked out for Pcmt1. This work shows that zebrafish is a promising model to unravel further facets of PCMT function and demonstrates, for the first time in vivo, that PCMT plays a pivotal role in the regulation of calcium fluxes.

Neuroimage in Psychiatry - What Can we See?

2009 ◽  
Vol 24 (S1) ◽  
pp. 1-1
Author(s):  
M. Mateus ◽  
C. Silva ◽  
O. Nogueiro ◽  
J. Redondo
Keyword(s):  
Neuropsychological Tests ◽  
Psychiatric Patients ◽  
Loose Coupling ◽  
Anatomy And Physiology ◽  
Regional Specificity ◽  
The Many ◽  
And Function ◽  
The Mind ◽  
The Brain

In the 20th century, scientists attempted to limitate the workings of the mind onto the brain by detailing its anatomy and physiology. The task of localizing function, however, has proven to be very difficult than initially presumed, with almoust all regions of the brain subserving a variety of processes and having only loose coupling of structure and function. As we know, the majority of neuropsychological tests and the brain capacities they tap lack brain regional specificity. This is a complex and sophisticated problem, that gets much worse in the brain that is compounded significantly by damage or disease. However, in the past two decades, neuroimaging has rekindled and renewed enthusiasm for unraveling brain function. Recent studies of cerebral image show “in vivo” what had already been proven in the laboratory: there are multiples neuroquimical changes in cortical and subcortical areas of the brain in psychiatric patients.Amongst the many techniques and technologies that have been developed, functional magnetic resonance imaging (fMRI) has proven to be one of the most exciting and perhaps the most used. It has permitted unprecedented access to the living brain. The authors propose to do a brief review on the late descoverys and studys that have been done with neuroimage.

Dopamine-loaded poly (butyl cyanoacrylate) nanoparticles reverse behavioral deficits in Parkinson’s animal models

2020 ◽  
Vol 11 (6) ◽  
pp. 387-399 ◽  
Author(s):  
Fatemeh Jahansooz ◽  
Bahman Ebrahimi Hosseinzade ◽  
Ashrafalsadat Hatamian Zarmi ◽  
Fatemeh Hadi ◽  
Seyed Mohammad Massood Hojjati ◽  
...  
Keyword(s):  
Animal Models ◽  
Delivery System ◽  
Behavioral Deficits ◽  
Brain Structure And Function ◽  
Pass Through ◽  
And Function ◽  
Drug Efficiency ◽  
The Brain ◽  
Impaired Motor Function

Aim: Parkinson's disease (PD) is a neurological disorder resulting from decreased dopamine (DA) secretion in the brain, which reflects impaired motor function. Thus, a drug-delivery system for releasing DA into the brain would be of crucial importance. Materials & methods: We herein examined the in vivo drug efficiency of novel poly-butyl-cyanoacrylate nanoparticles loaded with DA (DA-PBCA NPs). Results & conclusion: The NPs were able to pass through the blood–brain barrier and improve brain structure and function in the PD animal models. Moreover, we found a reduced α-synucleinopathy in the animal model brains after the NPs administration. Thus, the NPs seem to be a reliable DA delivery system for treating PD patients.

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