16 results on '"Kolisnyk, Benjamin"'
Search Results
2. The SATB1‐MIR22‐GBA axis mediates glucocerebroside accumulation inducing a cellular senescence‐like phenotype in dopaminergic neurons.
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Russo, Taylor, Kolisnyk, Benjamin, B. S., Aswathy, Plessis‐Belair, Jonathan, Kim, Tae Wan, Martin, Jacqueline, Ni, Jason, Pearson, Jordan A., Park, Emily J., Sher, Roger B., Studer, Lorenz, and Riessland, Markus
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DOPAMINERGIC neurons , *PARKINSON'S disease , *CELLULAR aging , *PHENOTYPES , *SUBSTANTIA nigra , *REGULATOR genes , *DOPAMINE receptors - Abstract
Idiopathic Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, which is associated with neuroinflammation and reactive gliosis. The underlying cause of PD and the concurrent neuroinflammation are not well understood. In this study, we utilize human and murine neuronal lines, stem cell‐derived dopaminergic neurons, and mice to demonstrate that three previously identified genetic risk factors for PD, namely SATB1, MIR22HG, and GBA, are components of a single gene regulatory pathway. Our findings indicate that dysregulation of this pathway leads to the upregulation of glucocerebrosides (GluCer), which triggers a cellular senescence‐like phenotype in dopaminergic neurons. Specifically, we discovered that downregulation of the transcriptional repressor SATB1 results in the derepression of the microRNA miR‐22‐3p, leading to decreased GBA expression and subsequent accumulation of GluCer. Furthermore, our results demonstrate that an increase in GluCer alone is sufficient to impair lysosomal and mitochondrial function, thereby inducing cellular senescence. Dysregulation of the SATB1‐MIR22‐GBA pathway, observed in both PD patients and normal aging, leads to lysosomal and mitochondrial dysfunction due to the GluCer accumulation, ultimately resulting in a cellular senescence‐like phenotype in dopaminergic neurons. Therefore, our study highlights a novel pathway involving three genetic risk factors for PD and provides a potential mechanism for the senescence‐induced neuroinflammation and reactive gliosis observed in both PD and normal aging. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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3. Sperm storage in Hemidactylus mabouia: Morphological and ultrastructural aspects of a reproductive strategy
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Nogueira, Katiane de Oliveira Pinto Coelho, Sartori, Sirlene Souza Rodrigues, Araújo, Vinícius Albano, Neves, Clóvis Andrade, and Kolisnyk, Benjamin
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- 2015
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4. Regulation of Cognitive Processing by Hippocampal Cholinergic Tone
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Al-Onaizi, Mohammed A., Parfitt, Gustavo M., Kolisnyk, Benjamin, Law, Clayton S. H., Guzman, Monica S., Barros, Daniela Martí, Leung, Stan L., Prado, Marco A. M., and Prado, Vania F.
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- 2017
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5. α7 nicotinic ACh receptor-deficient mice exhibit sustained attention impairments that are reversed by β2 nicotinic ACh receptor activation
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Kolisnyk, Benjamin, Al-Onaizi, Mohammed A., Prado, Vania F., and Prado, Marco A. M.
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- 2015
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6. Cholinergic Surveillance over Hippocampal RNA Metabolism and Alzheimer's-Like Pathology.
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Kolisnyk, Benjamin, Al-Onaizi, Mohammed, Soreq, Lilach, Barbash, Shahar, Bekenstein, Uriya, Haberman, Nejc, Hanin, Geula, Kish, Maxine T., Silva, Jussemara Souza da, Fahnestock, Margaret, Ule, Jernej, Soreq, Hermona, Prado, Vania F., and Prado, Marco A. M.
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- 2017
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7. Cholinergic Regulation of hnRNPA2/B1 Translation by M1 Muscarinic Receptors.
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Kolisnyk, Benjamin, Al-Onaizi, Mohammed A., Xu, Jason, Parfitt, Gustavo M., Ostapchenko, Valeriy G., Hanin, Geula, Soreq, Hermona, Prado, Marco A. M., and Prado, Vania F.
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MUSCARINIC receptors , *CHOLINERGIC receptors , *ACETYLCHOLINE , *ALZHEIMER'S disease , *GENE expression - Abstract
Cholinergic vulnerability, characterized by loss of acetylcholine (ACh), is one of the hallmarks of Alzheimer's disease (AD). Previous work has suggested that decreasedAChactivity inADmaycontribute to pathological changes through global alterations in alternative splicing. This occurs, at least partially, via the regulation of the expression of a critical protein family in RNA processing, heterogeneous nuclear ribonucleoprotein (hnRNP) A/B proteins. These proteins regulate several steps of RNA metabolism, including alternative splicing, RNA trafficking, miRNA export, and gene expression, providing multilevel surveillance in RNA functions. To investigate the mechanism by which cholinergic tone regulates hnRNPA2/B1 expression, we used a combination of genetic mouse models and in vivo and in vitro techniques. Decreasing cholinergic tone reduced levels of hnRNPA2/B1, whereas increasing cholinergic signaling in vivo increased expression of hnRNPA2/B1. This effect was not due to decreased hnRNPA2/B1mRNAexpression, increased aggregation, or degradation of the protein, but rather to decreased mRNA translation by nonsense-mediated decay regulation of translation. Cell culture and knockout mice experiments demonstrated that M1 muscarinic signaling is critical for cholinergic control of hnRNPA2/B1 protein levels. Our experiments suggest an intricate regulation of hnRNPA2/B1 levels by cholinergic activity that interferes with alternative splicing in targeted neurons mimicking deficits found in AD. [ABSTRACT FROM AUTHOR]
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- 2016
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8. Forebrain Deletion of the Vesicular Acetylcholine Transporter Results in Deficits in Executive Function, Metabolic, and RNA Splicing Abnormalities in the Prefrontal Cortex.
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Kolisnyk, Benjamin, Al-Onaizi, Mohammed A., Hirata, Pedro H. F., Guzman, Monica S., Nikolova, Simona, Barbash, Shahar, Soreq, Hermona, Bartha, Robert, Prado, Marco A. M., and Prado, Vania F.
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RNA splicing , *PREFRONTAL cortex , *EXECUTIVE function , *ACETYLCHOLINESTERASE , *ACETYLCHOLINE , *METABOLISM , *PROSENCEPHALON , *VISUAL discrimination - Abstract
Oneof the key brain regions in cognitive processing and executive function is the prefrontal cortex (PFC), which receives cholinergic input from basal forebrain cholinergic neurons. We evaluated the contribution of synaptically released acetylcholine (ACh) to executive function by genetically targeting the vesicular acetylcholine transporter (VAChT) in the mouse forebrain. Executive function was assessed using a pairwise visual discrimination paradigm and the 5-choice serial reaction time task (5-CSRT). In the pairwise test, VAChTdeficient mice were able to learn, but were impaired in reversal learning, suggesting that these mice present cognitive inflexibility. Interestingly, VAChT-targeted mice took longer to reach criteria in the 5-CSRT. Although their performance was indistinguishable from that of control mice during low attentional demand, increased attentional demand revealed striking deficits in VAChT-deleted mice. Galantamine, a cholinesterase inhibitor used in Alzheimer's disease, significantly improved the performance of control mice, but not of VAChT-deficient mice on the 5-CSRT. In vivo magnetic resonance spectroscopy showed altered levels of two neurochemical markers of neuronal function, taurine and lactate, suggesting altered PFC metabolism in VAChT-deficient mice. The PFC of these mice displayed a drastic reduction in the splicing factor heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1), whose cholinergic-mediated reduction was previously demonstrated in Alzheimer's disease. Consequently, several key hnRNPA2/B1 target transcripts involved in neuronal function present changes in alternative splicing in VAChT-deficient mice, including pyruvate kinase M, a key enzyme involved in lactate metabolism. We propose that VAChT-targeted mice can be used to model and to dissect the neurochemical basis of executive abnormalities. [ABSTRACT FROM AUTHOR]
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- 2013
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9. ChA T-ChR2-EYFP Mice Have Enhanced Motor Endurance But Show Deficits in Attention and Several Additional Cognitive Domains.
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Kolisnyk, Benjamin, Guzman, Monica S., Raulic, Sanda, Fan, Jue, Magalhaes, Ana C., Feng, Guoping, Gros, Robert, Prado, Vania F., and Prado, Marco A. M.
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ACETYLCHOLINE , *GROWTH associated protein-43 , *LABORATORY mice , *COGNITIVE neuroscience , *GENE expression , *RHODOPSIN , *ATTENTION-deficit hyperactivity disorder - Abstract
Acetylcholine (ACh) is an important neuromodulator in the nervous system implicated in many forms of cognitive and motor processing. Recent studies have used bacterial artificial chromosome (BAC) transgenic mice expressing channelrhodopsin-2 (ChR2) protein under the control of the choline acetyltransferase (Ch AT) promoter (ChA T-ChR2-EYFP) to dissect cholinergic circuit connectivity and function using optogenetic approaches. We report that a mouse line used for this purpose also carries several copies of the vesicular acetylcholine transporter gene (VAChT), which leads to overexpression of functional VAChT and consequently increased cholinergic tone. We dem-onstrate that these mice have marked improvement in motor endurance. However, they also present severe cognitive deficits, including attention deficits and dysfunction in working memory and spatial memory. These results suggest that increased VAChT expression may disrupt critical steps in information processing. Our studies demonstrate that ChA T-ChR2-EYFP mice show altered cholinergic tone that fundamentally differentiates them from wild-type mice. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
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10. Regulation of cholinergic activity by the vesicular acetylcholine transporter.
- Author
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PRADO, Vania F., ROY, Ashbeel, KOLISNYK, Benjamin, GROS, Robert, and PRADO, Marco A. M.
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ACETYLCHOLINE ,NEUROTRANSMITTERS ,CHOLINERGIC mechanisms ,SYNAPTIC vesicles ,NEURONS ,NEUROCHEMISTRY - Abstract
Acetylcholine, the first chemical to be identified as a neurotransmitter, is packed in synaptic vesicles by the activity of VAChT (vesicular acetylcholine transporter). A decrease in VAChT expression has been reported in a number of diseases, and this has consequences for the amount of acetylcholine loaded in synaptic vesicles as well as for neurotransmitter release. Several genetically modified mice targeting the VAChT gene have been generated, providing novel models to understand how changes in VAChT affect transmitter release.Asurprising finding is that most cholinergic neurons in the brain also can express a second type of vesicular neurotransmitter transporter that allows these neurons to secrete two distinct neurotransmitters. Thus a given neuron can use two neurotransmitters to regulate different physiological functions. In addition, recent data indicate that non-neuronal cells can also express the machinery used to synthesize and release acetylcholine. Some of these cells rely on VAChT to secrete acetylcholine with potential physiological consequences in the periphery. Hence novel functions for the oldest neurotransmitter known are emerging with the potential to provide new targets for the treatment of several pathological conditions. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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11. Reactive Dopamine Leads to Triple Trouble in Nigral Neurons.
- Author
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Riessland, Markus, Kolisnyk, Benjamin, and Greengard, Paul
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- 2017
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12. The SATB1-MIR22-GBA axis mediates glucocerebroside accumulation inducing a cellular senescence-like phenotype in dopaminergic neurons.
- Author
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Russo T, Kolisnyk B, Aswathy BS, Wan Kim T, Martin J, Plessis-Belair J, Ni J, Pearson JA, Park EJ, Sher RB, Studer L, and Riessland M
- Abstract
Idiopathic Parkinson's Disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, which is associated with neuroinflammation and reactive gliosis. The underlying cause of PD and the concurrent neuroinflammation are not well understood. In this study, we utilized human and murine neuronal lines, stem cell-derived dopaminergic neurons, and mice to demonstrate that three previously identified genetic risk factors for PD, namely SATB1, MIR22HG, and GBA, are components of a single gene regulatory pathway. Our findings indicate that dysregulation of this pathway leads to the upregulation of glucocerebrosides (GluCer), which triggers a cellular senescence-like phenotype in dopaminergic neurons. Specifically, we discovered that downregulation of the transcriptional repressor SATB1 results in the derepression of the microRNA miR-22-3p, leading to decreased GBA expression and subsequent accumulation of GluCer. Furthermore, our results demonstrate that an increase in GluCer alone is sufficient to impair lysosomal and mitochondrial function, thereby inducing cellular senescence dependent on S100A9 and stress factors. Dysregulation of the SATB1-MIR22-GBA pathway, observed in both PD patients and normal aging, leads to lysosomal and mitochondrial dysfunction due to the GluCer accumulation, ultimately resulting in a cellular senescence-like phenotype in dopaminergic neurons. Therefore, our study highlights a novel pathway involving three genetic risk factors for PD and provides a potential mechanism for the senescence-induced neuroinflammation and reactive gliosis observed in both PD and normal aging.
- Published
- 2023
- Full Text
- View/download PDF
13. TNF-NFkB-p53 axis restricts in vivo survival of hPSC-derived dopamine neuron.
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Kim TW, Koo SY, Riessland M, Cho H, Chaudhry F, Kolisnyk B, Russo MV, Saurat N, Mehta S, Garippa R, Betel D, and Studer L
- Abstract
Ongoing, first-in-human clinical trials illustrate the feasibility and translational potential of human pluripotent stem cell (hPSC)-based cell therapies in Parkinson's disease (PD). However, a major unresolved challenge in the field is the extensive cell death following transplantation with <10% of grafted dopamine neurons surviving. Here, we performed a pooled CRISPR/Cas9 screen to enhance survival of postmitotic dopamine neurons in vivo . We identified p53-mediated apoptotic cell death as major contributor to dopamine neuron loss and uncovered a causal link of TNFa-NFκB signaling in limiting cell survival. As a translationally applicable strategy to purify postmitotic dopamine neurons, we performed a cell surface marker screen that enabled purification without the need for genetic reporters. Combining cell sorting with adalimumab pretreatment, a clinically approved and widely used TNFa inhibitor, enabled efficient engraftment of postmitotic dopamine neurons leading to extensive re-innervation and functional recovery in a preclinical PD mouse model. Thus, transient TNFa inhibition presents a clinically relevant strategy to enhance survival and enable engraftment of postmitotic human PSC-derived dopamine neurons in PD., Highlights: In vivo CRISPR-Cas9 screen identifies p53 limiting survival of grafted human dopamine neurons. TNFα-NFκB pathway mediates p53-dependent human dopamine neuron deathCell surface marker screen to enrich human dopamine neurons for translational use. FDA approved TNF-alpha inhibitor rescues in vivo dopamine neuron survival with in vivo function.
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- 2023
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14. MouseBytes, an open-access high-throughput pipeline and database for rodent touchscreen-based cognitive assessment.
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Beraldo FH, Palmer D, Memar S, Wasserman DI, Lee WV, Liang S, Creighton SD, Kolisnyk B, Cowan MF, Mels J, Masood TS, Fodor C, Al-Onaizi MA, Bartha R, Gee T, Saksida LM, Bussey TJ, Strother SS, Prado VF, Winters BD, and Prado MA
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- Alzheimer Disease, Animals, Behavior, Animal, Choice Behavior, Databases, Factual, Disease Models, Animal, Female, Learning physiology, Male, Memory physiology, Mice, Neuropsychological Tests, Reproducibility of Results, Software, Cognition physiology, Laboratory Animal Science instrumentation, Laboratory Animal Science methods, Rodentia genetics
- Abstract
Open Science has changed research by making data accessible and shareable, contributing to replicability to accelerate and disseminate knowledge. However, for rodent cognitive studies the availability of tools to share and disseminate data is scarce. Automated touchscreen-based tests enable systematic cognitive assessment with easily standardised outputs that can facilitate data dissemination. Here we present an integration of touchscreen cognitive testing with an open-access database public repository (mousebytes.ca), as well as a Web platform for knowledge dissemination (https://touchscreencognition.org). We complement these resources with the largest dataset of age-dependent high-level cognitive assessment of mouse models of Alzheimer's disease, expanding knowledge of affected cognitive domains from male and female mice of three strains. We envision that these new platforms will enhance sharing of protocols, data availability and transparency, allowing meta-analysis and reuse of mouse cognitive data to increase the replicability/reproducibility of datasets., Competing Interests: FB, DP, SM, DW, WL, SL, SC, BK, MC, JM, TM, CF, MA, RB, TG, SS, VP, BW, MP No competing interests declared, LS Lisa Saksida has established a series of targeted cognitive tests for animals, administered via touchscreen within a custom environment known as the “Bussey-Saksida touchscreen chamber”. Cambridge Enterprise, the technology transfer office of the University of Cambridge, supported commercialization of the Bussey-Saksida chamber, culminating in a license to Campden Instruments. Any financial compensation received from commercialization of the technology is fully invested in further touchscreen development and/or maintenance, TB Tim Bussey has established a series of targeted cognitive tests for animals, administered via touchscreen within a custom environment known as the “Bussey-Saksida touchscreen chamber”. Cambridge Enterprise, the technology transfer office of the University of Cambridge, supported commercialization of the Bussey-Saksida chamber, culminating in a license to Campden Instruments. Any financial compensation received from commercialization of the technology is fully invested in further touchscreen development and/or maintenance, (© 2019, Beraldo et al.)
- Published
- 2019
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15. Loss of SATB1 Induces p21-Dependent Cellular Senescence in Post-mitotic Dopaminergic Neurons.
- Author
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Riessland M, Kolisnyk B, Kim TW, Cheng J, Ni J, Pearson JA, Park EJ, Dam K, Acehan D, Ramos-Espiritu LS, Wang W, Zhang J, Shim JW, Ciceri G, Brichta L, Studer L, and Greengard P
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- Animals, Cells, Cultured, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p21 genetics, Epigenetic Repression, Gene Knockdown Techniques, Humans, Matrix Attachment Region Binding Proteins genetics, Mice, Mice, Knockout, Mitosis, Parkinson Disease genetics, Protein Binding, Aging physiology, Cyclin-Dependent Kinase Inhibitor p21 metabolism, Dopaminergic Neurons physiology, Matrix Attachment Region Binding Proteins metabolism, Parkinson Disease metabolism
- Abstract
Cellular senescence is a mechanism used by mitotic cells to prevent uncontrolled cell division. As senescent cells persist in tissues, they cause local inflammation and are harmful to surrounding cells, contributing to aging. Generally, neurodegenerative diseases, such as Parkinson's, are disorders of aging. The contribution of cellular senescence to neurodegeneration is still unclear. SATB1 is a DNA binding protein associated with Parkinson's disease. We report that SATB1 prevents cellular senescence in post-mitotic dopaminergic neurons. Loss of SATB1 causes activation of a cellular senescence transcriptional program in dopamine neurons both in human stem cell-derived dopaminergic neurons and in mice. We observed phenotypes that are central to cellular senescence in SATB1 knockout dopamine neurons in vitro and in vivo. Moreover, we found that SATB1 directly represses expression of the pro-senescence factor p21 in dopaminergic neurons. Our data implicate senescence of dopamine neurons as a contributing factor in the pathology of Parkinson's disease., (Copyright © 2019 Elsevier Inc. All rights reserved.)
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- 2019
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16. Hyperactivity and attention deficits in mice with decreased levels of stress-inducible phosphoprotein 1 (STIP1).
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Beraldo FH, Thomas A, Kolisnyk B, Hirata PH, De Jaeger X, Martyn AC, Fan J, Goncalves DF, Cowan MF, Masood T, Martins VR, Gros R, Prado VF, and Prado MA
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- Animals, Attention Deficit Disorder with Hyperactivity genetics, Attention Deficit Disorder with Hyperactivity psychology, Disease Models, Animal, Genetic Predisposition to Disease, HSP70 Heat-Shock Proteins metabolism, HSP90 Heat-Shock Proteins metabolism, Heat-Shock Proteins genetics, Male, Maze Learning, Mice, Inbred C57BL, Mice, Knockout, Motor Activity, Phenotype, PrPC Proteins metabolism, Reaction Time, Swimming, Time Factors, Attention Deficit Disorder with Hyperactivity metabolism, Behavior, Animal, Heat-Shock Proteins deficiency
- Abstract
Stress-inducible phosphoprotein I (STIP1, STI1 or HOP) is a co-chaperone intermediating Hsp70/Hsp90 exchange of client proteins, but it can also be secreted to trigger prion protein-mediated neuronal signaling. Some mothers of children with autism spectrum disorders (ASD) present antibodies against certain brain proteins, including antibodies against STIP1. Maternal antibodies can cross the fetus blood-brain barrier during pregnancy, suggesting the possibility that they can interfere with STIP1 levels and, presumably, functions. However, it is currently unknown whether abnormal levels of STIP1 have any impact in ASD-related behavior. Here, we used mice with reduced (50%) or increased STIP1 levels (fivefold) to test for potential ASD-like phenotypes. We found that increased STIP1 regulates the abundance of Hsp70 and Hsp90, whereas reduced STIP1 does not affect Hsp70, Hsp90 or the prion protein. Interestingly, BAC transgenic mice presenting fivefold more STIP1 show no major phenotype when examined in a series of behavioral tasks, including locomotor activity, elevated plus maze, Morris water maze and five-choice serial reaction time task (5-CSRTT). In contrast, mice with reduced STIP1 levels are hyperactive and have attentional deficits on the 5-CSRTT, but exhibit normal performance for the other tasks. We conclude that reduced STIP1 levels can contribute to phenotypes related to ASD. However, future experiments are needed to define whether it is decreased chaperone capacity or impaired prion protein signaling that contributes to these phenotypes., (© 2015. Published by The Company of Biologists Ltd.)
- Published
- 2015
- Full Text
- View/download PDF
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