scholarly journals Calcium Signaling and Mitochondrial Function in Presenilin 2 Knock-Out Mice: Looking for Any Loss-of-Function Phenotype Related to Alzheimer’s Disease

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 204
Author(s):  
Alice Rossi ◽  
Luisa Galla ◽  
Chiara Gomiero ◽  
Lorena Zentilin ◽  
Mauro Giacca ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Neurodegenerative Disorder ◽  
Presenilin 1 ◽  
Loss Of Function ◽  
Catalytic Core ◽  
Knock Out ◽  
Age Related ◽  
Presenilin 2 ◽  
Knock Out Mice ◽  
Organelle Morphology

Alzheimer′s disease (AD) is the most common age-related neurodegenerative disorder in which learning, memory and cognitive functions decline progressively. Familial forms of AD (FAD) are caused by mutations in amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes. Presenilin 1 (PS1) and its homologue, presenilin 2 (PS2), represent, alternatively, the catalytic core of the γ-secretase complex that, by cleaving APP, produces neurotoxic amyloid beta (Aβ) peptides responsible for one of the histopathological hallmarks in AD brains, the amyloid plaques. Recently, PSEN1 FAD mutations have been associated with a loss-of-function phenotype. To investigate whether this finding can also be extended to PSEN2 FAD mutations, we studied two processes known to be modulated by PS2 and altered by FAD mutations: Ca2+ signaling and mitochondrial function. By exploiting neurons derived from a PSEN2 knock-out (PS2–/–) mouse model, we found that, upon IP3-generating stimulation, cytosolic Ca2+ handling is not altered, compared to wild-type cells, while mitochondrial Ca2+ uptake is strongly compromised. Accordingly, PS2–/– neurons show a marked reduction in endoplasmic reticulum–mitochondria apposition and a slight alteration in mitochondrial respiration, whereas mitochondrial membrane potential, and organelle morphology and number appear unchanged. Thus, although some alterations in mitochondrial function appear to be shared between PS2–/– and FAD-PS2-expressing neurons, the mechanisms leading to these defects are quite distinct between the two models. Taken together, our data appear to be difficult to reconcile with the proposal that FAD-PS2 mutants are loss-of-function, whereas the concept that PS2 plays a key role in sustaining mitochondrial function is here confirmed.

Increased Inflammatory Response Both in Brain and in Periphery in Presenilin 1 and Presenilin 2 Conditional Double Knock-Out Mice

2009 ◽  
Vol 18 (3) ◽  
pp. 515-523 ◽  
Author(s):  
Xu Jiang ◽  
Dongli Zhang ◽  
Jianting Shi ◽  
Yiqun Chen ◽  
Ping Zhang ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Presenilin 1 ◽  
Knock Out ◽  
Presenilin 2 ◽  
Knock Out Mice

scholarly journals NADPH Oxidase 2 Mediates Myocardial Oxygen Wasting in Obesity

Antioxidants ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 171 ◽  
Author(s):  
Anne D. Hafstad ◽  
Synne S. Hansen ◽  
Jim Lund ◽  
Celio X. C. Santos ◽  
Neoma T. Boardman ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Mitochondrial Function ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Mechanical Efficiency ◽  
Ros Production ◽  
Knock Out ◽  
Obesity And Diabetes ◽  
Mitochondrial Ros ◽  
Nadph Oxidase 2 ◽  
Knock Out Mice

Obesity and diabetes are independent risk factors for cardiovascular diseases, and they are associated with the development of a specific cardiomyopathy with elevated myocardial oxygen consumption (MVO2) and impaired cardiac efficiency. Although the pathophysiology of this cardiomyopathy is multifactorial and complex, reactive oxygen species (ROS) may play an important role. One of the major ROS-generating enzymes in the cardiomyocytes is nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), and many potential systemic activators of NOX2 are elevated in obesity and diabetes. We hypothesized that NOX2 activity would influence cardiac energetics and/or the progression of ventricular dysfunction following obesity. Myocardial ROS content and mechanoenergetics were measured in the hearts from diet-induced-obese wild type (DIOWT) and global NOK2 knock-out mice (DIOKO) and in diet-induced obese C57BL/6J mice given normal water (DIO) or water supplemented with the NOX2-inhibitor apocynin (DIOAPO). Mitochondrial function and ROS production were also assessed in DIO and DIOAPO mice. This study demonstrated that ablation and pharmacological inhibition of NOX2 both improved mechanical efficiency and reduced MVO2 for non-mechanical cardiac work. Mitochondrial ROS production was also reduced following NOX2 inhibition, while cardiac mitochondrial function was not markedly altered by apocynin-treatment. Therefore, these results indicate a link between obesity-induced myocardial oxygen wasting, NOX2 activation, and mitochondrial ROS.

Age-related differences in MK-801 induced behaviors in dopamine D3 receptor knock out mice

2010 ◽  
Vol 627 (1-3) ◽  
pp. 177-184
Author(s):  
Alex V. Iarkov ◽  
Terry C. Der ◽  
Jeffrey N. Joyce
Keyword(s):  
Dopamine D3 Receptor ◽  
D3 Receptor ◽  
Knock Out ◽  
Mk 801 ◽  
Age Related ◽  
Dopamine D3 ◽  
Knock Out Mice

scholarly journals Inner ear pathology and loss of hearing in estrogen receptor-β deficient mice

2009 ◽  
Vol 201 (3) ◽  
pp. 397-406 ◽  
Author(s):  
Rusana Simonoska ◽  
Annika E Stenberg ◽  
Maoli Duan ◽  
Konstantin Yakimchuk ◽  
Anders Fridberger ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Inner Ear ◽  
Spiral Ganglion ◽  
Organ Of Corti ◽  
Auditory Brainstem ◽  
Estrogen Receptor Β ◽  
Knock Out ◽  
Age Related ◽  
Brainstem Response ◽  
Knock Out Mice

There are well known differences between males and females in hearing. In the present study, the role of estrogen receptor-β (ER-β; listed as ESR2 in the MGI Database) in hearing was investigated by comparing hearing and morphology of the inner ear in ER-β knock-out mice (ER-β−/−) with that of wild-type (WT) littermates. Hearing was analyzed with auditory brainstem response audiometry at 3 and 12 months. The ER-β−/− mice were deaf at 1 year of age, and the morphological analysis showed absence of hair cells and loss of the whole organ of Corti initiated in the basal turn of the cochlea. Furthermore, in ER-β−/−, but not in WT mice, the spiral ganglion was lacking many of its neurons. Immunostaining showed the presence of both ER-α (listed as ESR1 in the MGI Database) and ER-β in the nuclei of some neurons in the inner ear in WT mice, but no ER-β was found in the ER-β−/− mice as expected. ER-α staining was predominant in the nuclei of large neurons and ER-β in nuclei of small neurons and fibroblasts. These results reveal that both ERs are present in the inner ear at specific localizations suggesting subtype-specific functions. It is concluded that ER-β is important for the prevention of age-related hearing loss. These findings strengthen the hypothesis that estrogen has a direct effect on hearing functions.

scholarly journals NaV1.2 haploinsufficiency in Scn2a knock-out mice causes an autistic-like phenotype attenuated with age

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Isabelle Léna ◽  
Massimo Mantegazza
Keyword(s):  
Wide Spectrum ◽  
Autism Spectrum ◽  
Face Validity ◽  
Loss Of Function ◽  
Gene Encoding ◽  
Knock Out ◽  
Adult Mice ◽  
Ohtahara Syndrome ◽  
Knock Out Mice ◽  
Adolescent Period

Abstract Mutations of the SCN2A gene, encoding the voltage gated sodium channel NaV1.2, have been associated to a wide spectrum of epileptic disorders ranging from benign familial neonatal-infantile seizures to early onset epileptic encephalopathies such as Ohtahara syndrome. These phenotypes may be caused by either gain-of-function or loss-of-function mutations. More recently, loss-of-function SCN2A mutations have also been identified in patients with autism spectrum disorder (ASD) without overt epileptic phenotypes. Heterozygous Scn2a knock-out mice (Scn2a+/−) may be a model of this phenotype. Because ASD develops in childhood, we performed a detailed behavioral characterization of Scn2a+/− mice comparing the juvenile/adolescent period of development and adulthood. We used tasks relevant to ASD and the different comorbidities frequently found in this disorder, such as anxiety or intellectual disability. Our data demonstrate that young Scn2a+/− mice display autistic-like phenotype associated to impaired memory and reduced reactivity to stressful stimuli. Interestingly, these dysfunctions are attenuated with age since adult mice show only communicative deficits. Considering the clinical data available on patients with loss-of-function SCN2A mutations, our results indicate that Scn2a+/− mice constitute an ASD model with construct and face validity during the juvenile/adolescent period of development. However, more information about the clinical features of adult carriers of SCN2A mutations is needed to evaluate comparatively the phenotype of adult Scn2a+/− mice.

scholarly journals Cyclase-associated protein 1 is a binding partner of proprotein convertase subtilisin/kexin type-9 and is required for the degradation of low-density lipoprotein receptors by proprotein convertase subtilisin/kexin type-9

2019 ◽  
Vol 41 (2) ◽  
pp. 239-252 ◽  
Author(s):  
Hyun-Duk Jang ◽  
Sang Eun Lee ◽  
Jimin Yang ◽  
Hyun-Chae Lee ◽  
Dasom Shin ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Loss Of Function ◽  
Proprotein Convertase ◽  
Lysosomal Degradation ◽  
Knock Out ◽  
Binding Partner ◽  
Knock Out Mice

Abstract Aims Proprotein convertase subtilisin/kexin type-9 (PCSK9), a molecular determinant of low-density lipoprotein (LDL) receptor (LDLR) fate, has emerged as a promising therapeutic target for atherosclerotic cardiovascular diseases. However, the precise mechanism by which PCSK9 regulates the internalization and lysosomal degradation of LDLR is unknown. Recently, we identified adenylyl cyclase-associated protein 1 (CAP1) as a receptor for human resistin whose globular C-terminus is structurally similar to the C-terminal cysteine-rich domain (CRD) of PCSK9. Herein, we investigated the role of CAP1 in PCSK9-mediated lysosomal degradation of LDLR and plasma LDL cholesterol (LDL-C) levels. Methods and results The direct binding between PCSK9 and CAP1 was confirmed by immunoprecipitation assay, far-western blot, biomolecular fluorescence complementation, and surface plasmon resonance assay. Fine mapping revealed that the CRD of PCSK9 binds with the Src homology 3 binding domain (SH3BD) of CAP1. Two loss-of-function polymorphisms found in human PCSK9 (S668R and G670E in CRD) were attributed to a defective interaction with CAP1. siRNA against CAP1 reduced the PCSK9-mediated degradation of LDLR in vitro. We generated CAP1 knock-out mice and found that the viable heterozygous CAP1 knock-out mice had higher protein levels of LDLR and lower LDL-C levels in the liver and plasma, respectively, than the control mice. Mechanistic analysis revealed that PCSK9-induced endocytosis and lysosomal degradation of LDLR were mediated by caveolin but not by clathrin, and they were dependent on binding between CAP1 and caveolin-1. Conclusion We identified CAP1 as a new binding partner of PCSK9 and a key mediator of caveolae-dependent endocytosis and lysosomal degradation of LDLR.

scholarly journals SLC2A knockout mice deficient in ascorbic acid synthesis recapitulate aspects of arterial tortuosity syndrome and display mitochondrial respiration defects

2019 ◽  
Author(s):  
Annekatrien Boel ◽  
Joyce Burger ◽  
Marine Vanhomwegen ◽  
Aude Beyens ◽  
Marjolijn Renard ◽  
...  
Keyword(s):  
Ascorbic Acid ◽  
Glucose Transporter ◽  
Dehydroascorbic Acid ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Human Phenotype ◽  
Knock Out ◽  
Arterial Tortuosity ◽  
Arterial Tortuosity Syndrome ◽  
Knock Out Mice

AbstractArterial tortuosity syndrome (ATS) is a recessively inherited connective tissue disorder, mainly characterized by tortuosity and aneurysm formation of the major arteries. ATS is caused by loss-of-function mutations in SLC2A10, encoding the facilitative glucose transporter GLUT10. Former studies implicate GLUT10 in transport of dehydroascorbic acid, the oxidized form of ascorbic acid (AA). Mouse models carrying homozygous Slc2a10 missense mutations do not recapitulate the human phenotype. Since mice, in contrast to humans, are able to intracellularly synthesize AA, we generated a novel ATS mouse model, deficient for Slc2a10 as well as Gulo, which encodes for L-gulonolactone oxidase, an enzyme catalyzing the final step in AA biosynthesis in rodents. Gulo;Slc2a10 knock-out mice show mild phenotypic anomalies, which were absent in single knock-out controls. While Gulo;Slc2a10 knock-out mice do not fully phenocopy human ATS, histological and immunocytochemical analysis revealed compromised extracellular matrix formation. TGFβ signaling remained unaltered, while mitochondrial function was compromised in smooth muscle cells derived from Gulo;Slc2a10 knock-out mice. Altogether, our data add evidence that ATS is an ascorbate compartmentalization disorder, but additional factors underlying the observed phenotype in humans remain to be determined.

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