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Article: Large-scale proteomics analysis of five brain regions from Parkinson's disease patients with a GBA1 mutation.

Blumenreich, Shani / Nehushtan, Tamar / Kupervaser, Meital / Shalit, Tali / Gabashvili, Alexandra / Joseph, Tammar / Milenkovic, Ivan / Hardy, John / Futerman, Anthony H

NPJ Parkinson's disease

2024 Volume 10, Issue 1, Page(s) 33

Abstract: Despite being the second most common neurodegenerative disorder, little is known about Parkinson's disease (PD) pathogenesis. A number of genetic factors predispose towards PD, among them mutations in GBA1, which encodes the lysosomal enzyme acid-β- ... ...

Abstract	Despite being the second most common neurodegenerative disorder, little is known about Parkinson's disease (PD) pathogenesis. A number of genetic factors predispose towards PD, among them mutations in GBA1, which encodes the lysosomal enzyme acid-β-glucosidase. We now perform non-targeted, mass spectrometry based quantitative proteomics on five brain regions from PD patients with a GBA1 mutation (PD-GBA) and compare to age- and sex-matched idiopathic PD patients (IPD) and controls. Two proteins were differentially-expressed in all five brain regions whereas significant differences were detected between the brain regions, with changes consistent with loss of dopaminergic signaling in the substantia nigra, and activation of a number of pathways in the cingulate gyrus, including ceramide synthesis. Mitochondrial oxidative phosphorylation was inactivated in PD samples in most brain regions and to a larger extent in PD-GBA. This study provides a comprehensive large-scale proteomics dataset for the study of PD-GBA.
Language	English
Publishing date	2024-02-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	2819218-7
ISSN	2373-8057
ISSN	2373-8057
DOI	10.1038/s41531-024-00645-x
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Article ; Online: Conventional type 1 dendritic cells are essential for the development of primary biliary cholangitis.

Reuveni, Debby / Assi, Siwar / Gore, Yael / Brazowski, Eli / Leung, Patrick S C / Shalit, Tali / Gershwin, Merrill E / Zigmond, Ehud

Liver international : official journal of the International Association for the Study of the Liver

2024

Abstract: Background & aims: Primary biliary cholangitis (PBC) is a progressive-cholestatic autoimmune liver disease. Dendritic cells (DC) are professional antigen-presenting cells and their prominent presence around damaged bile ducts of PBC patients are ... ...

Abstract	Background & aims: Primary biliary cholangitis (PBC) is a progressive-cholestatic autoimmune liver disease. Dendritic cells (DC) are professional antigen-presenting cells and their prominent presence around damaged bile ducts of PBC patients are documented. cDC1 is a rare subset of DC known for its cross-presentation abilities and interleukin 12 production. Our aim was to assess the role of cDC1 in the pathogenesis of PBC. Methods: We utilized an inducible murine model of PBC and took advantage of the DC reporter mice Zbtb46 Results: Histopathology assessment demonstrated peri-portal inflammation in wild type (WT) mice, whereas only minor abnormalities were observed in Batf3 Conclusion: Our data illustrated the contribution the cDC1 subset in the pathogenesis of PBC and provides a novel direction for immune based cell-specific targeted therapeutic approach in PBC.
Language	English
Publishing date	2024-05-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	2102783-3
ISSN	1478-3231 ; 1478-3223
ISSN (online)	1478-3231
ISSN	1478-3223
DOI	10.1111/liv.15961
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Article: Differential gene expression in the calvarial and cortical bone of juvenile female mice.

Janssen, Jerome Nicolas / Kalev-Altman, Rotem / Shalit, Tali / Sela-Donenfeld, Dalit / Monsonego-Ornan, Efrat

Frontiers in endocrinology

2023 Volume 14, Page(s) 1127536

Abstract: Introduction: Both the calvarial and the cortical bones develop through intramembranous ossification, yet they have very different structures and functions. The calvaria enables the rapid while protected growth of the brain, whereas the cortical bone ... ...

Abstract	Introduction: Both the calvarial and the cortical bones develop through intramembranous ossification, yet they have very different structures and functions. The calvaria enables the rapid while protected growth of the brain, whereas the cortical bone takes part in locomotion. Both types of bones undergo extensive modeling during embryonic and post-natal growth, while bone remodeling is the most dominant process in adults. Their shared formation mechanism and their highly distinct functions raise the fundamental question of how similar or diverse the molecular pathways that act in each bone type are. Methods: To answer this question, we aimed to compare the transcriptomes of calvaria and cortices from 21-day old mice by bulk RNA-Seq analysis. Results: The results revealed clear differences in expression levels of genes related to bone pathologies, craniosynostosis, mechanical loading and bone-relevant signaling pathways like WNT and IHH, emphasizing the functional differences between these bones. We further discussed the less expected candidate genes and gene sets in the context of bone. Finally, we compared differences between juvenile and mature bone, highlighting commonalities and dissimilarities of gene expression between calvaria and cortices during post-natal bone growth and adult bone remodeling. Discussion: Altogether, this study revealed significant differences between the transcriptome of calvaria and cortical bones in juvenile female mice, highlighting the most important pathway mediators for the development and function of two different bone types that originate both through intramembranous ossification.
MeSH term(s)	Mice ; Female ; Animals ; Skull/metabolism ; Osteogenesis/genetics ; Bone Development/genetics ; Cortical Bone ; Gene Expression
Language	English
Publishing date	2023-06-12
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2023.1127536
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Article ; Online: Proteomics analysis of the brain from a Gaucher disease mouse identifies pathological pathways including a possible role for transglutaminase 1.

Blumenreich, Shani / Ben-Yashar, Doreen Padan / Shalit, Tali / Kupervaser, Meital / Milenkovic, Ivan / Joseph, Tammar / Futerman, Anthony H

Journal of neurochemistry

2023 Volume 168, Issue 1, Page(s) 52–65

Abstract: Gaucher disease (GD) is a lysosomal storage disorder (LSD) caused by the defective activity of acid β-glucosidase (GCase) which results from mutations in GBA1. Neurological forms of GD (nGD) can be generated in mice by intra-peritoneal injection of ... ...

Abstract	Gaucher disease (GD) is a lysosomal storage disorder (LSD) caused by the defective activity of acid β-glucosidase (GCase) which results from mutations in GBA1. Neurological forms of GD (nGD) can be generated in mice by intra-peritoneal injection of conduritol B-epoxide (CBE) which irreversibly inhibits GCase. Using this approach, a number of pathological pathways have been identified in mouse brain by RNAseq. However, unlike transcriptomics, proteomics gives direct information about protein expression which is more likely to provide insight into which cellular pathways are impacted in disease. We now perform non-targeted, mass spectrometry-based quantitative proteomics on brains from mice injected with 50 mg/kg body weight CBE for 13 days. Of the 5038 detected proteins, 472 were differentially expressed between control and CBE-injected mice of which 104 were selected for further analysis based on higher stringency criteria. We also compared these proteins with differentially expressed genes (DEGs) identified by RNAseq. Some lysosomal proteins were up-regulated as was interferon signaling, whereas levels of ion channel related proteins and some proteins associated with neurotransmitter signaling were reduced, as was cholesterol metabolism. One protein, transglutaminase 1 (TGM1), which is elevated in a number of neurodegenerative diseases, was absent from the control group but was found at high levels in CBE-injected mice, and located in the extracellular matrix (ECM) in layer V of the cortex and intracellularly in Purkinje cells in the cerebellum. Together, the proteomics data confirm previous RNAseq data and add additional mechanistic understanding about cellular pathways that may play a role in nGD pathology.
MeSH term(s)	Animals ; Mice ; Gaucher Disease/metabolism ; Proteomics ; Glucosylceramidase/genetics ; Brain/metabolism ; Transglutaminases/genetics ; Transglutaminases/metabolism
Chemical Substances	transglutaminase 1 (EC 2.3.2.13) ; Glucosylceramidase (EC 3.2.1.45) ; Transglutaminases (EC 2.3.2.13)
Language	English
Publishing date	2023-12-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80158-6
ISSN	1471-4159 ; 0022-3042 ; 1474-1644
ISSN (online)	1471-4159
ISSN	0022-3042 ; 1474-1644
DOI	10.1111/jnc.16024
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Article ; Online: Heterochronic regulation of lung development

Komarovsky Gulman, Nelly / Armon, Leah / Shalit, Tali / Urbach, Achia

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2019 Volume 33, Issue 11, Page(s) 12008–12018

Abstract: The heterochronic gene Lin28 regulates diverse developmental processes. It was shown previously that global Lin28A overexpression during mouse embryogenesis results in perinatal lethality. However, the reason for this early lethality has not been ... ...

Abstract	The heterochronic gene Lin28 regulates diverse developmental processes. It was shown previously that global Lin28A overexpression during mouse embryogenesis results in perinatal lethality. However, the reason for this early lethality has not been elucidated. Here, we showed that Lin28A overexpression prevents normal lung development
MeSH term(s)	Animals ; Cell Differentiation/genetics ; Cell Proliferation/genetics ; Cluster Analysis ; Embryonic Development/genetics ; Female ; Gene Expression Profiling/methods ; Gene Expression Regulation, Developmental ; Lung/cytology ; Lung/embryology ; Lung/metabolism ; Mesenchymal Stem Cells/cytology ; Mesenchymal Stem Cells/metabolism ; Mice, Transgenic ; MicroRNAs/genetics ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; Signal Transduction/genetics ; Time Factors
Chemical Substances	Lin-28 protein, mouse ; MicroRNAs ; RNA-Binding Proteins ; mirnlet7 microRNA, mouse
Language	English
Publishing date	2019-08-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.201802702R
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Zs.A 2266: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: The Toll Pathway in the Central Nervous System of Flies and Mammals.

Shmueli, Anat / Shalit, Tali / Okun, Eitan / Shohat-Ophir, Galit

Neuromolecular medicine

2018 Volume 20, Issue 4, Page(s) 419–436

Abstract: Toll receptors, first identified to regulate embryogenesis and immune responses in the adult fly and subsequently defined as the principal sensors of infection in mammals, are increasingly appreciated for their impact on the homeostasis of the central as ...

Abstract	Toll receptors, first identified to regulate embryogenesis and immune responses in the adult fly and subsequently defined as the principal sensors of infection in mammals, are increasingly appreciated for their impact on the homeostasis of the central as well as the peripheral nervous systems. Whereas in the context of immunity, the fly Toll and the mammalian TLR pathways have been researched in parallel, the expression pattern and functionality have largely been researched disparately. Herein, we provide data on the expression pattern of the Toll homologues, signaling components, and downstream effectors in ten different cell populations of the adult fly central nervous system (CNS). We have compared the expression of the different Toll pathways in the fly to the expression of TLRs in the mouse brain and discussed the implications with respect to commonalities, differences, and future perspectives.
MeSH term(s)	Animals ; Brain/metabolism ; Central Nervous System/immunology ; Central Nervous System/metabolism ; Drosophila Proteins/genetics ; Drosophila Proteins/physiology ; Drosophila melanogaster/genetics ; Drosophila melanogaster/immunology ; Drosophila melanogaster/metabolism ; Gene Expression Regulation ; Mice/immunology ; Mice/metabolism ; Nerve Tissue Proteins/metabolism ; Neuroglia/metabolism ; Neurons/metabolism ; Pathogen-Associated Molecular Pattern Molecules/metabolism ; RNA, Messenger/biosynthesis ; Signal Transduction ; Species Specificity ; Toll-Like Receptors/genetics ; Toll-Like Receptors/physiology
Chemical Substances	Drosophila Proteins ; Nerve Tissue Proteins ; Pathogen-Associated Molecular Pattern Molecules ; RNA, Messenger ; Toll-Like Receptors ; spz protein, Drosophila
Language	English
Publishing date	2018-10-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2077809-0
ISSN	1559-1174 ; 1535-1084
ISSN (online)	1559-1174
ISSN	1535-1084
DOI	10.1007/s12017-018-8515-9
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Article ; Online: β-sitosterol reduces anxiety and synergizes with established anxiolytic drugs in mice.

Panayotis, Nicolas / Freund, Philip A / Marvaldi, Letizia / Shalit, Tali / Brandis, Alexander / Mehlman, Tevie / Tsoory, Michael M / Fainzilber, Mike

Cell reports. Medicine

2021 Volume 2, Issue 5, Page(s) 100281

Abstract: Anxiety and stress-related conditions represent a significant health burden in modern society. Unfortunately, most anxiolytic drugs are prone to side effects, limiting their long-term usage. Here, we employ a bioinformatics screen to identify drugs for ... ...

Abstract	Anxiety and stress-related conditions represent a significant health burden in modern society. Unfortunately, most anxiolytic drugs are prone to side effects, limiting their long-term usage. Here, we employ a bioinformatics screen to identify drugs for repurposing as anxiolytics. Comparison of drug-induced gene-expression profiles with the hippocampal transcriptome of an importin α5 mutant mouse model with reduced anxiety identifies the hypocholesterolemic agent β-sitosterol as a promising candidate. β-sitosterol activity is validated by both intraperitoneal and oral application in mice, revealing it as the only clear anxiolytic from five closely related phytosterols. β-sitosterol injection reduces the effects of restraint stress, contextual fear memory, and c-Fos activation in the prefrontal cortex and dentate gyrus. Moreover, synergistic anxiolysis is observed when combining sub-efficacious doses of β-sitosterol with the SSRI fluoxetine. These preclinical findings support further development of β-sitosterol, either as a standalone anxiolytic or in combination with low-dose SSRIs.
MeSH term(s)	Animals ; Anti-Anxiety Agents/pharmacology ; Anxiety/drug therapy ; Anxiety Disorders/drug therapy ; Fear/drug effects ; Fluoxetine/pharmacology ; Mice, Inbred C57BL ; Motor Activity/drug effects ; Pharmaceutical Preparations/metabolism ; Prefrontal Cortex/drug effects ; Proto-Oncogene Proteins c-fos/pharmacology ; Selective Serotonin Reuptake Inhibitors/pharmacology ; Sitosterols/pharmacology ; Tranquilizing Agents/pharmacology ; Mice
Chemical Substances	Anti-Anxiety Agents ; Pharmaceutical Preparations ; Proto-Oncogene Proteins c-fos ; Serotonin Uptake Inhibitors ; Sitosterols ; Tranquilizing Agents ; Fluoxetine (01K63SUP8D) ; gamma-sitosterol (5LI01C78DD)
Language	English
Publishing date	2021-05-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2666-3791
ISSN (online)	2666-3791
DOI	10.1016/j.xcrm.2021.100281
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Article: Genomic structural plasticity of rodent‐associated Bartonella in nature

de Sousa, Keyla Carstens Marques / Gutiérrez, Ricardo / Yahalomi, Dayana / Shalit, Tali / Markus, Barak / Nachum‐Biala, Yaarit / Hawlena, Hadas / Marcos‐Hadad, Evgeniya / Hazkani‐Covo, Einat / de Rezende Neves, Haroldo Henrique / Covo, Shay / Harrus, Shimon

Molecular ecology. 2022 July, v. 31, no. 14

2022

Abstract: Rodent‐associated Bartonella species have shown a remarkable genetic diversity and pathogenic potential. To further explore the extent of the natural intraspecific genomic variation and its potential role as an evolutionary driver, we focused on a single ...

Abstract	Rodent‐associated Bartonella species have shown a remarkable genetic diversity and pathogenic potential. To further explore the extent of the natural intraspecific genomic variation and its potential role as an evolutionary driver, we focused on a single genetically diverse Bartonella species, Bartonella krasnovii, which circulates among gerbils and their associated fleas. Twenty genomes from 16 different B. krasnovii genotypes were fully characterized through a genome sequencing assay (using short and long read sequencing), pulse field gel electrophoresis (PFGE), and PCR validation. Genomic analyses were performed in comparison to the B. krasnovii strain OE 1–1. While, single nucleotide polymorphism represented only a 0.3% of the genome variation, structural diversity was identified in these genomes, with an average of 51 ± 24 structural variation (SV) events per genome. Interestingly, a large proportion of the SVs (>40%) was associated with prophages. Further analyses revealed that most of the SVs, and prophage insertions were found at the chromosome replication termination site (ter), suggesting this site as a plastic zone of the B. krasnovii chromosome. Accordingly, six genomes were found to be unbalanced, and essential genes near the ter showed a shift between the leading and lagging strands, revealing the SV effect on these genomes. In summary, our findings demonstrate the extensive genomic diversity harbored by wild B. krasnovii strains and suggests that its diversification is initially promoted by structural changes, probably driven by phages. These events may constantly feed the system with novel genotypes that ultimately lead to inter‐ and intraspecies competition and adaptation.
Keywords	Bartonella ; chromosomes ; ecology ; genetic variation ; genomics ; pathogenicity ; pulsed-field gel electrophoresis ; single nucleotide polymorphism
Language	English
Dates of publication	2022-07
Size	p. 3784-3797.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	JOURNAL ARTICLE
ZDB-ID	1126687-9
ISSN	1365-294X ; 0962-1083
ISSN (online)	1365-294X
ISSN	0962-1083
DOI	10.1111/mec.16547
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Article ; Online: Genomic structural plasticity of rodent-associated Bartonella in nature.

de Sousa, Keyla Carstens Marques / Gutiérrez, Ricardo / Yahalomi, Dayana / Shalit, Tali / Markus, Barak / Nachum-Biala, Yaarit / Hawlena, Hadas / Marcos-Hadad, Evgeniya / Hazkani-Covo, Einat / de Rezende Neves, Haroldo Henrique / Covo, Shay / Harrus, Shimon

Molecular ecology

2022 Volume 31, Issue 14, Page(s) 3784–3797

Abstract: Rodent-associated Bartonella species have shown a remarkable genetic diversity and pathogenic potential. To further explore the extent of the natural intraspecific genomic variation and its potential role as an evolutionary driver, we focused on a single ...

Abstract	Rodent-associated Bartonella species have shown a remarkable genetic diversity and pathogenic potential. To further explore the extent of the natural intraspecific genomic variation and its potential role as an evolutionary driver, we focused on a single genetically diverse Bartonella species, Bartonella krasnovii, which circulates among gerbils and their associated fleas. Twenty genomes from 16 different B. krasnovii genotypes were fully characterized through a genome sequencing assay (using short and long read sequencing), pulse field gel electrophoresis (PFGE), and PCR validation. Genomic analyses were performed in comparison to the B. krasnovii strain OE 1-1. While, single nucleotide polymorphism represented only a 0.3% of the genome variation, structural diversity was identified in these genomes, with an average of 51 ± 24 structural variation (SV) events per genome. Interestingly, a large proportion of the SVs (>40%) was associated with prophages. Further analyses revealed that most of the SVs, and prophage insertions were found at the chromosome replication termination site (ter), suggesting this site as a plastic zone of the B. krasnovii chromosome. Accordingly, six genomes were found to be unbalanced, and essential genes near the ter showed a shift between the leading and lagging strands, revealing the SV effect on these genomes. In summary, our findings demonstrate the extensive genomic diversity harbored by wild B. krasnovii strains and suggests that its diversification is initially promoted by structural changes, probably driven by phages. These events may constantly feed the system with novel genotypes that ultimately lead to inter- and intraspecies competition and adaptation.
MeSH term(s)	Animals ; Bartonella/genetics ; Bartonella Infections ; Genomics/methods ; Gerbillinae ; Siphonaptera/genetics
Language	English
Publishing date	2022-06-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1126687-9
ISSN	1365-294X ; 0962-1083
ISSN (online)	1365-294X
ISSN	0962-1083
DOI	10.1111/mec.16547
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Article ; Online: Bartonella kosoyi

Gutiérrez, Ricardo / Shalit, Tali / Markus, Barak / Yuan, Congli / Nachum-Biala, Yaarit / Elad, Daniel / Harrus, Shimon

International journal of systematic and evolutionary microbiology

2020 Volume 70, Issue 3, Page(s) 1656–1665

Abstract: ... The ... ...

Abstract	The genus
MeSH term(s)	Animals ; Bacterial Typing Techniques ; Bartonella/classification ; Bartonella/isolation & purification ; Base Composition ; DNA, Bacterial/genetics ; Fatty Acids/chemistry ; Israel ; Phylogeny ; RNA, Ribosomal, 16S/genetics ; Rats/microbiology ; Sequence Analysis, DNA ; Siphonaptera/microbiology
Chemical Substances	DNA, Bacterial ; Fatty Acids ; RNA, Ribosomal, 16S
Language	English
Publishing date	2020-02-25
Publishing country	England
Document type	Journal Article
ZDB-ID	2002336-4
ISSN	1466-5034 ; 1466-5026
ISSN (online)	1466-5034
ISSN	1466-5026
DOI	10.1099/ijsem.0.003952
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