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Article ; Online: Extracellular vesicle-associated small heat shock proteins as therapeutic agents in neurodegenerative diseases and beyond.

Van den Broek, Bram / Wuyts, Charlotte / Irobi, Joy

2021 Volume 179, Page(s) 114009

Abstract: Increasing evidence points towards using extracellular vesicles (EVs) as a therapeutic strategy in neurodegenerative diseases such as multiple sclerosis, Parkinson's, and Alzheimer's disease. EVs are nanosized carriers that play an essential role in ... ...

Abstract	Increasing evidence points towards using extracellular vesicles (EVs) as a therapeutic strategy in neurodegenerative diseases such as multiple sclerosis, Parkinson's, and Alzheimer's disease. EVs are nanosized carriers that play an essential role in intercellular communication and cellular homeostasis by transporting an active molecular cargo, including a large variety of proteins. Recent publications demonstrate that small heat shock proteins (HSPBs) exhibit a beneficial role in neurodegenerative diseases. Moreover, it is defined that HSPBs target the autophagy and the apoptosis pathway, playing a prominent role in chaperone activity and cell survival. This review elaborates on the therapeutic potential of EVs and HSPBs, in particular HSPB1 and HSPB8, in neurodegenerative diseases. We conclude that EVs and HSPBs positively influence neuroinflammation, central nervous system (CNS) repair, and protein aggregation in CNS disorders. Moreover, we propose the use of HSPB-loaded EVs as advanced nanocarriers for the future development of neurodegenerative disease therapies.
MeSH term(s)	Apoptosis/drug effects ; Apoptosis/physiology ; Autophagy/drug effects ; Autophagy/physiology ; Central Nervous System Diseases/drug therapy ; Central Nervous System Diseases/physiopathology ; Drug Carriers ; Extracellular Vesicles/metabolism ; Heat-Shock Proteins, Small/pharmacology ; Heat-Shock Proteins, Small/therapeutic use ; Humans ; Inflammation/physiopathology ; Nanoparticle Drug Delivery System/pharmacology ; Nanoparticle Drug Delivery System/therapeutic use ; Neurodegenerative Diseases/drug therapy ; Neurodegenerative Diseases/physiopathology
Chemical Substances	Drug Carriers ; Heat-Shock Proteins, Small ; Nanoparticle Drug Delivery System
Language	English
Publishing date	2021-10-18
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	639113-8
ISSN	1872-8294 ; 0169-409X
ISSN (online)	1872-8294
ISSN	0169-409X
DOI	10.1016/j.addr.2021.114009
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Article ; Online: Extracellular vesicle-associated lipids in central nervous system disorders.

Vanherle, Sam / Haidar, Mansour / Irobi, Joy / Bogie, Jeroen F J / Hendriks, Jerome J A

Advanced drug delivery reviews

2020 Volume 159, Page(s) 322–331

Abstract: Increasing evidence indicates that lipid metabolism is disturbed in central nervous system (CNS) disorders, such as multiple sclerosis, Alzheimer's, and Parkinson's disease. Extracellular vesicles (EVs), including exosomes and microvesicles, are ... ...

Abstract	Increasing evidence indicates that lipid metabolism is disturbed in central nervous system (CNS) disorders, such as multiple sclerosis, Alzheimer's, and Parkinson's disease. Extracellular vesicles (EVs), including exosomes and microvesicles, are nanosized particles that play an essential role in intercellular communication and tissue homeostasis by transporting diverse biologically active molecules, including a large variety of lipid species. In the last decade, studies defined that changes in the EV lipidome closely correlate with disease-progression and -remission in CNS disorders. In this review, we summarize and discuss these changes in the EV lipidome and elaborate on the impact of different EV-associated lipids on pathological processes in CNS disorders. We conclude that EV-associated lipids are closely associated with neuroinflammation, CNS repair, and pathological protein aggregation in CNS disorders, and that modulation of the EV lipidome represents a promising therapeutic strategy to halt disease progression in multiple sclerosis, Alzheimer's, and Parkinson's disease. Moreover, we predict that disease-stage specific EV-associated lipid signatures can be invaluable markers for the diagnosis and early detection of CNS disorders in the future.
MeSH term(s)	Animals ; Central Nervous System Diseases/metabolism ; Extracellular Vesicles/metabolism ; Humans ; Lipid Metabolism ; Lipids
Chemical Substances	Lipids
Language	English
Publishing date	2020-05-01
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	639113-8
ISSN	1872-8294 ; 0169-409X
ISSN (online)	1872-8294
ISSN	0169-409X
DOI	10.1016/j.addr.2020.04.011
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Article ; Online: Oligodendroglia-derived extracellular vesicles activate autophagy via LC3B/BAG3 to protect against oxidative stress with an enhanced effect for HSPB8 enriched vesicles.

Van den Broek, Bram / Wuyts, Charlotte / Sisto, Angela / Pintelon, Isabel / Timmermans, Jean-Pierre / Somers, Veerle / Timmerman, Vincent / Hellings, Niels / Irobi, Joy

Cell communication and signaling : CCS

2022 Volume 20, Issue 1, Page(s) 58

Abstract: Background: The contribution of native or modified oligodendroglia-derived extracellular vesicles (OL-EVs) in controlling chronic inflammation is poorly understood. In activated microglia, OL-EVs contribute to the removal of cytotoxic proteins following ...

Abstract	Background: The contribution of native or modified oligodendroglia-derived extracellular vesicles (OL-EVs) in controlling chronic inflammation is poorly understood. In activated microglia, OL-EVs contribute to the removal of cytotoxic proteins following a proteotoxic stress. Intracellular small heat shock protein B8 (HSPB8) sustain this function by facilitating autophagy and protecting cells against oxidative stress mediated cell death. Therefore, secretion of HSPB8 in OL-EVs could be beneficial for neurons during chronic inflammation. However, how secreted HSPB8 contribute to cellular proteostasis remains to be elucidated. Methods: We produced oligodendroglia-derived EVs, either native (OL-EVs) or HSPB8 modified (OL-HSPB8-EVs), to investigate their effects in controlling chronic inflammation and cellular homeostasis. We analyzed the impact of both EV subsets on either a resting or activated microglial cell line and on primary mixed neural cell culture cells. Cells were activated by stimulating with either tumor necrosis factor-alpha and interleukin 1-beta or with phorbol-12-myristate-13-acetate. Results: We show that OL-EVs and modified OL-HSPB8-EVs are internalized by C20 microglia and by primary mixed neural cells. The cellular uptake of OL-HSPB8-EVs increases the endogenous HSPB8 mRNA expression. Consistently, our results revealed that both EV subsets maintained cellular homeostasis during chronic inflammation with an increase in the formation of autophagic vesicles. Both EV subsets conveyed LC3B-II and BAG3 autophagy markers with an enhanced effect observed for OL-HSPB8-EVs. Moreover, stimulation with either native or modified OL-HSPB8-EVs showed a significant reduction in ubiquitinated protein, reactive oxygen species and mitochondrial depolarization, with OL-HSPB8-EVs exhibiting a more protective effect. Both EV subsets did not induce cell death in the C20 microglia cell line or the primary mixed neural cultures. Conclusion: We demonstrate that the functions of oligodendroglia secreted EVs enriched with HSPB8 have a supportive role, comparable to the native OL-EVs. Further development of engineered oligodendroglia derived EVs could be a novel therapeutic strategy in countering chronic inflammation. Video Abstract.
MeSH term(s)	Adaptor Proteins, Signal Transducing/metabolism ; Apoptosis Regulatory Proteins/metabolism ; Autophagy ; Extracellular Vesicles/metabolism ; Heat-Shock Proteins/metabolism ; Humans ; Inflammation/metabolism ; Molecular Chaperones/metabolism ; Oligodendroglia/metabolism ; Oligodendroglia/pathology ; Oxidative Stress
Chemical Substances	Adaptor Proteins, Signal Transducing ; Apoptosis Regulatory Proteins ; BAG3 protein, human ; HSPB8 protein, human ; Heat-Shock Proteins ; Molecular Chaperones
Language	English
Publishing date	2022-05-05
Publishing country	England
Document type	Journal Article ; Video-Audio Media ; Research Support, Non-U.S. Gov't
ZDB-ID	2126315-2
ISSN	1478-811X ; 1478-811X
ISSN (online)	1478-811X
ISSN	1478-811X
DOI	10.1186/s12964-022-00863-x
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Article ; Online: Angiogenic Effects of Human Dental Pulp and Bone Marrow-Derived Mesenchymal Stromal Cells and their Extracellular Vesicles.

Merckx, Greet / Hosseinkhani, Baharak / Kuypers, Sören / Deville, Sarah / Irobi, Joy / Nelissen, Inge / Michiels, Luc / Lambrichts, Ivo / Bronckaers, Annelies

Cells

2020 Volume 9, Issue 2

Abstract: Blood vessel formation or angiogenesis is a key process for successful tooth regeneration. Bone marrow-derived mesenchymal stromal cells (BM-MSCs) possess paracrine proangiogenic properties, which are, at least partially, induced by their extracellular ... ...

Abstract	Blood vessel formation or angiogenesis is a key process for successful tooth regeneration. Bone marrow-derived mesenchymal stromal cells (BM-MSCs) possess paracrine proangiogenic properties, which are, at least partially, induced by their extracellular vesicles (EVs). However, the isolation of BM-MSCs is associated with several drawbacks, which could be overcome by MSC-like cells of the teeth, called dental pulp stromal cells (DPSCs). This study aims to compare the angiogenic content and functions of DPSC and BM-MSC EVs and conditioned medium (CM). The angiogenic protein profile of DPSC- and BM-MSC-derived EVs, CM and EV-depleted CM was screened by an antibody array and confirmed by ELISA. Functional angiogenic effects were tested in transwell migration and chicken chorioallantoic membrane assays. All secretion fractions contained several pro- and anti-angiogenic proteins and induced in vitro endothelial cell motility. This chemotactic potential was higher for (EV-depleted) CM, compared to EVs with a stronger effect for BM-MSCs. Finally, BM-MSC CM, but not DPSC CM, nor EVs, increased in ovo angiogenesis. In conclusion, we showed that DPSCs are less potent in relation to endothelial cell chemotaxis and in ovo neovascularization, compared to BM-MSCs, which emphasizes the importance of choice of cell type and secretion fraction for stem cell-based regenerative therapies in inducing angiogenesis.
MeSH term(s)	Adolescent ; Angiogenesis Inducing Agents/metabolism ; Animals ; Chemotactic Factors/pharmacology ; Chickens ; Dental Pulp/cytology ; Endocytosis/drug effects ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; Extracellular Vesicles/drug effects ; Extracellular Vesicles/metabolism ; Extracellular Vesicles/ultrastructure ; Female ; Humans ; Male ; Mesenchymal Stem Cells/drug effects ; Mesenchymal Stem Cells/metabolism ; Mesenchymal Stem Cells/ultrastructure ; Neovascularization, Physiologic/drug effects ; Paracrine Communication/drug effects ; Time Factors ; Young Adult
Chemical Substances	Angiogenesis Inducing Agents ; Chemotactic Factors
Language	English
Publishing date	2020-01-28
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells9020312
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Article ; Online: Oligodendroglia-derived extracellular vesicles activate autophagy via LC3B/BAG3 to protect against oxidative stress with an enhanced effect for HSPB8 enriched vesicles

Bram Van den Broek / Charlotte Wuyts / Angela Sisto / Isabel Pintelon / Jean-Pierre Timmermans / Veerle Somers / Vincent Timmerman / Niels Hellings / Joy Irobi

Cell Communication and Signaling, Vol 20, Iss 1, Pp 1-

2022 Volume 19

Abstract: Abstract Background The contribution of native or modified oligodendroglia-derived extracellular vesicles (OL-EVs) in controlling chronic inflammation is poorly understood. In activated microglia, OL-EVs contribute to the removal of cytotoxic proteins ... ...

Abstract	Abstract Background The contribution of native or modified oligodendroglia-derived extracellular vesicles (OL-EVs) in controlling chronic inflammation is poorly understood. In activated microglia, OL-EVs contribute to the removal of cytotoxic proteins following a proteotoxic stress. Intracellular small heat shock protein B8 (HSPB8) sustain this function by facilitating autophagy and protecting cells against oxidative stress mediated cell death. Therefore, secretion of HSPB8 in OL-EVs could be beneficial for neurons during chronic inflammation. However, how secreted HSPB8 contribute to cellular proteostasis remains to be elucidated. Methods We produced oligodendroglia-derived EVs, either native (OL-EVs) or HSPB8 modified (OL-HSPB8-EVs), to investigate their effects in controlling chronic inflammation and cellular homeostasis. We analyzed the impact of both EV subsets on either a resting or activated microglial cell line and on primary mixed neural cell culture cells. Cells were activated by stimulating with either tumor necrosis factor-alpha and interleukin 1-beta or with phorbol-12-myristate-13-acetate. Results We show that OL-EVs and modified OL-HSPB8-EVs are internalized by C20 microglia and by primary mixed neural cells. The cellular uptake of OL-HSPB8-EVs increases the endogenous HSPB8 mRNA expression. Consistently, our results revealed that both EV subsets maintained cellular homeostasis during chronic inflammation with an increase in the formation of autophagic vesicles. Both EV subsets conveyed LC3B-II and BAG3 autophagy markers with an enhanced effect observed for OL-HSPB8-EVs. Moreover, stimulation with either native or modified OL-HSPB8-EVs showed a significant reduction in ubiquitinated protein, reactive oxygen species and mitochondrial depolarization, with OL-HSPB8-EVs exhibiting a more protective effect. Both EV subsets did not induce cell death in the C20 microglia cell line or the primary mixed neural cultures. Conclusion We demonstrate that the functions of oligodendroglia secreted EVs enriched ...
Keywords	CNS ; Engineered nanocarriers ; Extracellular vesicles ; Microglia ; Molecular chaperones ; Cellular inflammation ; Medicine ; R ; Cytology ; QH573-671
Subject code	610
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
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Article ; Online: Angiogenic Effects of Human Dental Pulp and Bone Marrow-Derived Mesenchymal Stromal Cells and their Extracellular Vesicles

Greet Merckx / Baharak Hosseinkhani / Sören Kuypers / Sarah Deville / Joy Irobi / Inge Nelissen / Luc Michiels / Ivo Lambrichts / Annelies Bronckaers

Cells, Vol 9, Iss 2, p

2020 Volume 312

Abstract	Blood vessel formation or angiogenesis is a key process for successful tooth regeneration. Bone marrow-derived mesenchymal stromal cells (BM-MSCs) possess paracrine proangiogenic properties, which are, at least partially, induced by their extracellular vesicles (EVs). However, the isolation of BM-MSCs is associated with several drawbacks, which could be overcome by MSC-like cells of the teeth, called dental pulp stromal cells (DPSCs). This study aims to compare the angiogenic content and functions of DPSC and BM-MSC EVs and conditioned medium (CM). The angiogenic protein profile of DPSC- and BM-MSC-derived EVs, CM and EV-depleted CM was screened by an antibody array and confirmed by ELISA. Functional angiogenic effects were tested in transwell migration and chicken chorioallantoic membrane assays. All secretion fractions contained several pro- and anti-angiogenic proteins and induced in vitro endothelial cell motility. This chemotactic potential was higher for (EV-depleted) CM, compared to EVs with a stronger effect for BM-MSCs. Finally, BM-MSC CM, but not DPSC CM, nor EVs, increased in ovo angiogenesis. In conclusion, we showed that DPSCs are less potent in relation to endothelial cell chemotaxis and in ovo neovascularization, compared to BM-MSCs, which emphasizes the importance of choice of cell type and secretion fraction for stem cell-based regenerative therapies in inducing angiogenesis.
Keywords	extracellular vesicles ; bone marrow-derived mesenchymal stromal cells ; dental pulp stromal cells ; angiogenesis ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2020-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article: Microglial derived extracellular vesicles activate autophagy and mediate multi-target signaling to maintain cellular homeostasis.

Van den Broek, Bram / Pintelon, Isabel / Hamad, Ibrahim / Kessels, Sofie / Haidar, Mansour / Hellings, Niels / Hendriks, Jerome J A / Kleinewietfeld, Markus / Brône, Bert / Timmerman, Vincent / Timmermans, Jean-Pierre / Somers, Veerle / Michiels, Luc / Irobi, Joy

Journal of extracellular vesicles

2020 Volume 10, Issue 1, Page(s) e12022

Abstract: Microglia, the immunocompetent cells of the central nervous system (CNS), play an important role in maintaining cellular homeostasis in the CNS. These cells secrete immunomodulatory factors including nanovesicles and participate in the removal of ... ...

Abstract	Microglia, the immunocompetent cells of the central nervous system (CNS), play an important role in maintaining cellular homeostasis in the CNS. These cells secrete immunomodulatory factors including nanovesicles and participate in the removal of cellular debris by phagocytosis or autophagy. Accumulating evidence indicates that specifically the cellular exchange of small extracellular vesicles (EVs), participates in physiology and disease through intercellular communication. However, the contribution of microglial-derived extracellular vesicles (M-EVs) to the maintenance of microglia homeostasis and how M-EVs could influence the phenotype and gene function of other microglia subtypes is unclear. In addition, knowledge of canonical signalling pathways of inflammation and immunity gene expression patterns in human microglia exposed to M-EVs is limited. Here, we analysed the effects of M-EVs produced in vitro by either tumour necrosis factor alpha (TNFα) activated or non-activated microglia BV2 cells. We showed that M-EVs are internalized by both mouse and human C20 microglia cells and that the uptake of M-EVs in microglia induced autophagic vesicles at various stages of degradation including autophagosomes and autolysosomes. Consistently, stimulation of microglia with M-EVs increased the protein expression of the autophagy marker, microtubule-associated proteins 1A/1B light chain 3B isoform II (LC3B-II), and promoted autophagic flux in live cells. To elucidate the biological activities occurring at the transcriptional level in C20 microglia stimulated with M-EVs, the gene expression profiles, potential upstream regulators, and enrichment pathways were characterized using targeted RNA sequencing. Inflammation and immunity transcriptome gene panel sequencing of both activated and normal microglia stimulated with M-EVs showed involvement of several canonical pathways and reduced expression of key genes involved in neuroinflammation, inflammasome and apoptosis signalling pathways compared to control cells. In this study, we provide the perspective that a beneficial activity of in vitro cell culture produced EVs could be the modulation of autophagy during cellular stress. Therefore, we use a monoculture system to study microglia-microglia crosstalk which is important in the prevention and propagation of inflammation in the brain. We demonstrate that in vitro produced microglial EVs are able to influence multiple biological pathways and promote activation of autophagy in order to maintain microglia survival and homeostasis.
MeSH term(s)	Animals ; Autophagy ; Cell Line ; Extracellular Vesicles/metabolism ; Gene Expression Regulation ; Humans ; Mice ; Microglia/metabolism ; Microtubule-Associated Proteins/biosynthesis ; Signal Transduction
Chemical Substances	MAP1LC3B protein, human ; Map1lc3b protein, mouse ; Microtubule-Associated Proteins
Language	English
Publishing date	2020-11-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2683797-3
ISSN	2001-3078
ISSN	2001-3078
DOI	10.1002/jev2.12022
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Article ; Online: A knock-in/knock-out mouse model of HSPB8-associated distal hereditary motor neuropathy and myopathy reveals toxic gain-of-function of mutant Hspb8.

Bouhy, Delphine / Juneja, Manisha / Katona, Istvan / Holmgren, Anne / Asselbergh, Bob / De Winter, Vicky / Hochepied, Tino / Goossens, Steven / Haigh, Jody J / Libert, Claude / Ceuterick-de Groote, Chantal / Irobi, Joy / Weis, Joachim / Timmerman, Vincent

Acta neuropathologica

2017 Volume 135, Issue 1, Page(s) 131–148

Abstract: Mutations in the small heat shock protein B8 gene (HSPB8/HSP22) have been associated with distal hereditary motor neuropathy, Charcot-Marie-Tooth disease, and recently distal myopathy. It is so far not clear how mutant HSPB8 induces the neuronal and ... ...

Abstract	Mutations in the small heat shock protein B8 gene (HSPB8/HSP22) have been associated with distal hereditary motor neuropathy, Charcot-Marie-Tooth disease, and recently distal myopathy. It is so far not clear how mutant HSPB8 induces the neuronal and muscular phenotypes and if a common pathogenesis lies behind these diseases. Growing evidence points towards a role of HSPB8 in chaperone-associated autophagy, which has been shown to be a determinant for the clearance of poly-glutamine aggregates in neurodegenerative diseases but also for the maintenance of skeletal muscle myofibrils. To test this hypothesis and better dissect the pathomechanism of mutant HSPB8, we generated a new transgenic mouse model leading to the expression of the mutant protein (knock-in lines) or the loss-of-function (functional knock-out lines) of the endogenous protein Hspb8. While the homozygous knock-in mice developed motor deficits associated with degeneration of peripheral nerves and severe muscle atrophy corroborating patient data, homozygous knock-out mice had locomotor performances equivalent to those of wild-type animals. The distal skeletal muscles of the post-symptomatic homozygous knock-in displayed Z-disk disorganisation, granulofilamentous material accumulation along with Hspb8, αB-crystallin (HSPB5/CRYAB), and desmin aggregates. The presence of the aggregates correlated with reduced markers of effective autophagy. The sciatic nerve of the homozygous knock-in mice was characterized by low autophagy potential in pre-symptomatic and Hspb8 aggregates in post-symptomatic animals. On the other hand, the sciatic nerve of the homozygous knock-out mice presented a normal morphology and their distal muscle displayed accumulation of abnormal mitochondria but intact myofiber and Z-line organisation. Our data, therefore, suggest that toxic gain-of-function of mutant Hspb8 aggregates is a major contributor to the peripheral neuropathy and the myopathy. In addition, mutant Hspb8 induces impairments in autophagy that may aggravate the phenotype.
MeSH term(s)	Animals ; Atrophy/metabolism ; Atrophy/pathology ; Autophagy/physiology ; Disease Models, Animal ; Distal Myopathies/metabolism ; Distal Myopathies/pathology ; Female ; Gain of Function Mutation ; HSP20 Heat-Shock Proteins/genetics ; HSP20 Heat-Shock Proteins/metabolism ; Heat-Shock Proteins ; Mice, Transgenic ; Mitochondria/metabolism ; Mitochondria/pathology ; Molecular Chaperones ; Muscle Proteins/genetics ; Muscle Proteins/metabolism ; Muscle, Skeletal/metabolism ; Muscle, Skeletal/pathology ; Myopathies, Structural, Congenital/metabolism ; Myopathies, Structural, Congenital/pathology ; Peripheral Nervous System Diseases/metabolism ; Sciatic Nerve/metabolism ; Sciatic Nerve/pathology
Chemical Substances	HSP20 Heat-Shock Proteins ; Heat-Shock Proteins ; Hspb8 protein, mouse ; Molecular Chaperones ; Muscle Proteins
Language	English
Publishing date	2017-08-05
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1079-0
ISSN	1432-0533 ; 0001-6322
ISSN (online)	1432-0533
ISSN	0001-6322
DOI	10.1007/s00401-017-1756-0
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Article ; Online: Charcot-Marie-Tooth causing HSPB1 mutations increase Cdk5-mediated phosphorylation of neurofilaments.

Holmgren, Anne / Bouhy, Delphine / De Winter, Vicky / Asselbergh, Bob / Timmermans, Jean-Pierre / Irobi, Joy / Timmerman, Vincent

Acta neuropathologica

2013 Volume 126, Issue 1, Page(s) 93–108

Abstract: Mutations in the small heat shock protein HSPB1 (HSP27) are a cause of axonal Charcot-Marie-Tooth neuropathy (CMT2F) and distal hereditary motor neuropathy. To better understand the effect of mutations in HSPB1 on the neuronal cytoskeleton, we stably ... ...

Abstract	Mutations in the small heat shock protein HSPB1 (HSP27) are a cause of axonal Charcot-Marie-Tooth neuropathy (CMT2F) and distal hereditary motor neuropathy. To better understand the effect of mutations in HSPB1 on the neuronal cytoskeleton, we stably transduced neuronal cells with wild-type and mutant HSPB1 and investigated axonal transport of neurofilaments (NFs). We observed that mutant HSPB1 affected the binding of NFs to the anterograde motor protein kinesin, reducing anterograde transport of NFs. These deficits were associated with an increased phosphorylation of NFs and cyclin-dependent kinase Cdk5. As Cdk5 mediates NF phosphorylation, inhibition of Cdk5/p35 restored NF phosphorylation level, as well as NF binding to kinesin in mutant HSPB1 neuronal cells. Altogether, we demonstrate that HSPB1 mutations induce hyperphosphorylation of NFs through Cdk5 and reduce anterograde transport of NFs.
MeSH term(s)	Axonal Transport/genetics ; Axons/metabolism ; Axons/pathology ; Cell Line, Tumor ; Charcot-Marie-Tooth Disease/genetics ; Cyclin-Dependent Kinase 5/genetics ; Cyclin-Dependent Kinase 5/metabolism ; HSP27 Heat-Shock Proteins/genetics ; Heat-Shock Proteins ; Humans ; Immunoprecipitation ; Kinesin/metabolism ; Molecular Chaperones ; Mutation/genetics ; Neuroblastoma/pathology ; Neurofilament Proteins/metabolism ; Phosphorylation/genetics ; Transfection/methods
Chemical Substances	HSP27 Heat-Shock Proteins ; HSPB1 protein, human ; Heat-Shock Proteins ; Molecular Chaperones ; Neurofilament Proteins ; Cyclin-Dependent Kinase 5 (EC 2.7.11.1) ; Kinesin (EC 3.6.4.4)
Language	English
Publishing date	2013-06-01
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1079-0
ISSN	1432-0533 ; 0001-6322
ISSN (online)	1432-0533
ISSN	0001-6322
DOI	10.1007/s00401-013-1133-6
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Article: Molecular genetics of distal hereditary motor neuropathies.

Irobi, Joy / De Jonghe, Peter / Timmerman, Vincent

Human molecular genetics

2004 Volume 13 Spec No 2, Page(s) R195–202

Abstract: Inherited peripheral neuropathies comprise a wide variety of diseases primarily affecting the peripheral nervous system. The best-known peripheral neuropathy is Charcot-Marie-Tooth disease (CMT) described in 1886 by J.-M. Charcot, P. Marie and H.H. Tooth. ...

Abstract	Inherited peripheral neuropathies comprise a wide variety of diseases primarily affecting the peripheral nervous system. The best-known peripheral neuropathy is Charcot-Marie-Tooth disease (CMT) described in 1886 by J.-M. Charcot, P. Marie and H.H. Tooth. In 1980, A.E. Harding and P.K. Thomas showed that in a large group of individuals with CMT, several only had motor abnormalities on clinical and electrophysiological examination, whereas sensory abnormalities were absent. This exclusively motor variant of CMT was designated as spinal CMT or hereditary distal spinal muscular atrophy, and included in the distal hereditary motor neuropathies (distal HMN). The distal HMN are clinically and genetically heterogeneous and are subdivided according to the mode of inheritance, age at onset and clinical evolution. Since the introduction of positional cloning, 12 chromosomal loci and seven disease-causing genes have been identified for autosomal dominant and recessive distal HMN. Most of the genes involved have housekeeping functions, as in RNA processing, translation synthesis, glycosylation, stress response, apoptosis, but also axonal trafficking and editing. Functional characterization of the mutations will help to unravel the cellular processes that underlie the specificity of motor neuropathies leading to neurogenic muscular atrophy of distal limb muscles. Here we review the recent progress of the molecular genetics of distal HMN and discuss the genes implicated.
MeSH term(s)	Genetic Linkage/genetics ; Hereditary Sensory and Autonomic Neuropathies/genetics ; Humans ; Molecular Biology
Language	English
Publishing date	2004-10-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddh226
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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito