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Publications (10 of 12) Show all publications
Shteinfer-Kuzmine, A., Argueti, S., Gupta, R., Shvil, N., Abu-Hamad, S., Gropper, Y., . . . Israelson, A. (2019). A VDAC1-Derived N-Terminal Peptide Inhibits Mutant SOD1-VDAC1 Interactions and Toxicity in the SOD1 Model of ALS. Frontiers in Cellular Neuroscience, 13, Article ID 346.
Open this publication in new window or tab >>A VDAC1-Derived N-Terminal Peptide Inhibits Mutant SOD1-VDAC1 Interactions and Toxicity in the SOD1 Model of ALS
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2019 (English)In: Frontiers in Cellular Neuroscience, ISSN 1662-5102, E-ISSN 1662-5102, Vol. 13, article id 346Article in journal (Refereed) Published
Abstract [en]

Mutations in superoxide dismutase (SOD1) are the second most common cause of familial amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease caused by the death of motor neurons in the brain and spinal cord. SOD1 neurotoxicity has been attributed to aberrant accumulation of misfolded SOD1, which in its soluble form binds to intracellular organelles, such as mitochondria and ER, disrupting their functions. Here, we demonstrate that mutant SOD1 binds specifically to the N-terminal domain of the voltage-dependent anion channel (VDAC1), an outer mitochondrial membrane protein controlling cell energy, metabolic and survival pathways. Mutant SOD1(G93A) and SOD1(G85R), but not wild type SOD1, directly interact with VDAC1 and reduce its channel conductance. No such interaction with N-terminal-truncated VDAC1 occurs. Moreover, a VDAC1-derived N-terminal peptide inhibited mutant SOD1-induced toxicity. Incubation of motor neuron-like NSC-34 cells expressing mutant SOD1 or mouse embryonic stem cell-derived motor neurons with different VDAC1 N-terminal peptides resulted in enhanced cell survival. Taken together, our results establish a direct link between mutant SOD1 toxicity and the VDAC1 N-terminal domain and suggest that VDAC1 N-terminal peptides targeting mutant SOD1 provide potential new therapeutic strategies for ALS.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2019
Keywords
ALS, misfolded SOD1, mutant SOD1, N-terminal peptide, VDAC1
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-393659 (URN)10.3389/fncel.2019.00346 (DOI)000480746900001 ()
Available from: 2019-09-25 Created: 2019-09-25 Last updated: 2019-09-25Bibliographically approved
Schizas, N., König, N., Andersson, B., Vasylovska, S., Hoeber, J., Kozlova, E. & Hailer, N. (2018). Neural crest stem cells protect spinal cord neurons from excitotoxic damage and inhibit glial activation by secretion of brain-derived neurotrophic factor. Cell and Tissue Research, 372(3), 493-505
Open this publication in new window or tab >>Neural crest stem cells protect spinal cord neurons from excitotoxic damage and inhibit glial activation by secretion of brain-derived neurotrophic factor
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2018 (English)In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 372, no 3, p. 493-505Article in journal (Refereed) Published
Abstract [en]

The acute phase of spinal cord injury is characterized by excitotoxic and inflammatory events that mediate extensive neuronal loss in the gray matter. Neural crest stem cells (NCSCs) can exert neuroprotective and anti-inflammatory effects that may be mediated by soluble factors. We therefore hypothesize that transplantation of NCSCs to acutely injured spinal cord slice cultures (SCSCs) can prevent neuronal loss after excitotoxic injury. NCSCs were applied onto SCSCs previously subjected to N-methyl-d-aspartate (NMDA)-induced injury. Immunohistochemistry and TUNEL staining were used to quantitatively study cell populations and apoptosis. Concentrations of neurotrophic factors were measured by ELISA. Migration and differentiation properties of NCSCs on SCSCs, laminin, or hyaluronic acid hydrogel were separately studied. NCSCs counteracted the loss of NeuN-positive neurons that was otherwise observed after NMDA-induced excitotoxicity, partly by inhibiting neuronal apoptosis. They also reduced activation of both microglial cells and astrocytes. The concentration of brain-derived neurotrophic factor (BDNF) was increased in supernatants from SCSCs cultured with NCSCs compared to SCSCs alone and BDNF alone mimicked the effects of NCSC application on SCSCs. NCSCs migrated superficially across the surface of SCSCs and showed no signs of neuronal or glial differentiation but preserved their expression of SOX2 and Krox20. In conclusion, NCSCs exert neuroprotective, anti-apoptotic and glia-inhibitory effects on excitotoxically injured spinal cord tissue, some of these effects mediated by secretion of BDNF. However, the investigated NCSCs seem not to undergo neuronal or glial differentiation in the short term since markers indicative of an undifferentiated state were expressed during the entire observation period.

Keywords
Neuroprotection, Suppressed glial activation, Excitotoxicity, Apoptosis, Secretion of soluble factors
National Category
Cell Biology
Identifiers
urn:nbn:se:uu:diva-356852 (URN)10.1007/s00441-018-2808-z (DOI)000432109000004 ()29516218 (PubMedID)
Funder
Swedish Research Council, 20716Stiftelsen Olle Engkvist Byggmästare
Available from: 2018-08-16 Created: 2018-08-16 Last updated: 2018-08-16Bibliographically approved
Hoeber, J., König, N., Trolle, C., Lekholm, E., Zhou, C., Pankratova, S., . . . Kozlova, E. (2017). A Combinatorial Approach to Induce Sensory Axon Regeneration into the Dorsal Root Avulsed Spinal Cord. Stem Cells and Development, 26(14), 1065-1077
Open this publication in new window or tab >>A Combinatorial Approach to Induce Sensory Axon Regeneration into the Dorsal Root Avulsed Spinal Cord
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2017 (English)In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 26, no 14, p. 1065-1077Article in journal (Refereed) Published
Abstract [en]

Spinal root injuries result in newly formed glial scar formation, which prevents regeneration of sensory axons causing permanent sensory loss. Previous studies showed that delivery of trophic factors or implantation of human neural progenitor cells supports sensory axon regeneration and partly restores sensory functions. In this study, we elucidate mechanisms underlying stem cell-mediated ingrowth of sensory axons after dorsal root avulsion (DRA). We show that human spinal cord neural stem/progenitor cells (hscNSPC), and also, mesoporous silica particles loaded with growth factor mimetics (MesoMIM), supported sensory axon regeneration. However, when hscNSPC and MesoMIM were combined, sensory axon regeneration failed. Morphological and tracing analysis showed that sensory axons grow through the newly established glial scar along "bridges" formed by migrating stem cells. Coimplantation of MesoMIM prevented stem cell migration, "bridges" were not formed, and sensory axons failed to enter the spinal cord. MesoMIM applied alone supported sensory axons ingrowth, but without affecting glial scar formation. In vitro, the presence of MesoMIM significantly impaired migration of hscNSPC without affecting their level of differentiation. Our data show that (1) the ability of stem cells to migrate into the spinal cord and organize cellular "bridges" in the newly formed interface is crucial for successful sensory axon regeneration, (2) trophic factor mimetics delivered by mesoporous silica may be a convenient alternative way to induce sensory axon regeneration, and (3) a combinatorial approach of individually beneficial components is not necessarily additive, but can be counterproductive for axonal growth.

Keywords
biomimetics, neural stem cells, spinal cord regeneration, stem cell transplantation
National Category
Neurosciences Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Hematology
Identifiers
urn:nbn:se:uu:diva-328587 (URN)10.1089/scd.2017.0019 (DOI)000405071200005 ()28562227 (PubMedID)
Funder
Stiftelsen Olle Engkvist ByggmästareSwedish Research Council, 20716
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2017-08-28 Created: 2017-08-28 Last updated: 2018-01-13Bibliographically approved
Trolle, C., Ivert, P., Hoeber, J., Rocamonde-Lago, I., Vasylovska, S., Lukanidin, E. & Kozlova, E. N. (2017). Boundary cap neural crest stem cell transplants contribute Mts1/S100A4-expressing cells in the glial scar. Regenerative Medicine, 12(4), 339-351
Open this publication in new window or tab >>Boundary cap neural crest stem cell transplants contribute Mts1/S100A4-expressing cells in the glial scar
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2017 (English)In: Regenerative Medicine, ISSN 1746-0751, E-ISSN 1746-076X, Vol. 12, no 4, p. 339-351Article in journal (Refereed) Published
Abstract [en]

AIM: During development, boundary cap neural crest stem cells (bNCSCs) assist sensory axon growth into the spinal cord. Here we repositioned them to test if they assist regeneration of sensory axons in adult mice after dorsal root avulsion injury.

MATERIALS & METHODS: Avulsed mice received bNCSC or human neural progenitor (hNP) cell transplants and their contributions to glial scar formation and sensory axon regeneration were analyzed with immunohistochemistry and transganglionic tracing.

RESULTS: hNPs and bNCSCs form similar gaps in the glial scar, but unlike hNPs, bNCSCs contribute Mts1/S100A4 (calcium-binding protein) expression to the scar and do not assist sensory axon regeneration.

CONCLUSION: bNCSC transplants contribute nonpermissive Mts1/S100A4-expressing cells to the glial scar after dorsal root avulsion.

Keywords
calcium-binding protein, glia, nerve degeneration, neural stem cell, sensory neuron, spinal cord
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-328589 (URN)10.2217/rme-2016-0163 (DOI)000406147100006 ()28621171 (PubMedID)
Funder
Swedish Research Council, 20716
Available from: 2017-08-28 Created: 2017-08-28 Last updated: 2018-01-13Bibliographically approved
Aggarwal, T., Hoeber, J., Ivert, P., Vasylovska, S. & Kozlova, E. (2017). Boundary Cap Neural Crest Stem Cells Promote Survival of Mutant SOD1 Motor Neurons. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 14(3), 773-783
Open this publication in new window or tab >>Boundary Cap Neural Crest Stem Cells Promote Survival of Mutant SOD1 Motor Neurons
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2017 (English)In: Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, ISSN 1878-7479, Vol. 14, no 3, p. 773-783Article in journal (Refereed) Published
Abstract [en]

ALS is a devastating disease resulting in degeneration of motor neurons (MNs) in the brain and spinal cord. The survival of MNs strongly depends on surrounding glial cells and neurotrophic support from muscles. We previously demonstrated that boundary cap neural crest stem cells (bNCSCs) can give rise to neurons and glial cells in vitro and in vivo and have multiple beneficial effects on co-cultured and co-implanted cells, including neural cells. In this paper, we investigate if bNCSCs may improve survival of MNs harboring a mutant form of human SOD1 (SOD1(G93A)) in vitro under normal conditions and oxidative stress and in vivo after implantation to the spinal cord. We found that survival of SOD1(G93A) MNs in vitro was increased in the presence of bNCSCs under normal conditions as well as under oxidative stress. In addition, when SOD1(G93A) MN precursors were implanted to the spinal cord of adult mice, their survival was increased when they were co-implanted with bNCSCs. These findings show that bNCSCs support survival of SOD1(G93A) MNs in normal conditions and under oxidative stress in vitro and improve their survival in vivo, suggesting that bNCSCs have a potential for the development of novel stem cell-based therapeutic approaches in ALS models.

Keywords
Amyotrophic lateral sclerosis, Neurodegeneration, Neuroglia, Oxidative stress, Transplantation
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-328588 (URN)10.1007/s13311-016-0505-8 (DOI)000405725300022 ()28070746 (PubMedID)
Funder
Swedish Research Council, 20716Stiftelsen Olle Engkvist Byggmästare
Available from: 2017-08-28 Created: 2017-08-28 Last updated: 2018-09-07Bibliographically approved
Hoeber, J. (2017). Neural progenitors for sensory and motor repair. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Neural progenitors for sensory and motor repair
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Injury and neurodegenerative conditions of the spinal cord can lead to paralysis and loss of sensation. Cell therapeutic approaches can restore sensory innervation of the spinal cord following injury and protect spinal cord cells from degeneration. This thesis primarily focuses on the restoration of deaffarented sensory fibres following injury to the dorsal root and spinal cord. These injuries lead to the formation of a non-permissive glial scar that prevents sensory axons from reinnervating spinal cord targets. It takes advantage of a dorsal root injury model that closely mimics spinal root avulsion injuries occurring in humans. In the first part of the thesis, three different neural progenitor types from human or murine sources are tested for their regenerative properties following their transplantation to the site of dorsal root avulsion injury. In the second part, the ability of murine neural progenitors to protect spinal motor neurons from a neurodegenerative process is tested.

In the first original research article, I show that human embryonic stem cell derived neural progenitors are able to restore sensorimotor functions, mediated by the formation of a tissue bridge that allows ingrowth of sensory axons into the spinal cord. In the second research article, I present that murine boundary cap neural crest stem cells, a special type of neural progenitor that governs the entry of sensory axons into the spinal cord during development, are unable to form a permissive tissue bridge. This is possibly caused by the contribution of transplant derived ingrowth non-permissive glial cells. In the third research article, I show that human neural progenitors derived from foetal sources are capable of stimulating sensory ingrowth and that they ameliorate the glial scar. When this approach is combined with the delivery of sensory outgrowth stimulating neurotrophic factors, these cells fail to form a permissive tissue bridge and fail to modify the glial scar. In the final research article, murine boundary cap neural crest stem cells are shown to protect motor neurons, which harbor an amyotrophic lateral sclerosis causing mutation, from oxidative stress. Oxidative stress is a pathological component of amyotrophic lateral sclerosis in human patients.

Taken together, this thesis provides first evidence that sensory regeneration following a spinal root avulsion injury can be achieved by transplantation of human neural progenitors. In addition, it introduces murine boundary cap neural crest stem cells as interesting candidates for the cell therapeutic treatment of amyotrophic lateral sclerosis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. p. 67
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1365
Keywords
Regenerative Neurobiology, Stem cells, Sensory regeneration, Spinal cord injury, Amyotrophic Lateral Sclerosis, Neurodegeneration, Oxidative Stress
National Category
Neurosciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-328590 (URN)978-91-513-0058-0 (ISBN)
Public defence
2017-10-23, B/C8:305, Husargatan 3, Uppsala, 10:00 (English)
Opponent
Supervisors
Available from: 2017-10-02 Created: 2017-08-31 Last updated: 2018-01-13
Hoeber, J. (2015). Generation of functional neural progenitors for spinal cord transplantation. (Licentiate dissertation). Uppsala: Uppsala University, Department of Neuroscience
Open this publication in new window or tab >>Generation of functional neural progenitors for spinal cord transplantation
2015 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Dorsal root avulsion injuries result in permanent impairment of sensory functions due to the disconnection of the peripheral nervous system from the spinal cord. Strategies aiming for the functional reconnection of sensory neurons with their targets in the spinal cord dorsal horn need to overcome the axonal growth non-permissive glial scar and provide a growth promoting environment. Stem cell therapy holds great promise in the context of root avulsion injuries as it combines the potential to provide a permissive and axonal growth attractive environment and the ability to form a neuronal relay between sensory neurons and spinal cord targets. In the first study, we show that human embryonic stem cell derived spinal cord neural progenitors(hNPs) restore sensorimotor functions in a model of dorsal root avulsion injury. The observed recovery of sensory functions was mediated by hNP cells forming growth permissive gates inthe glial scar that allowed spinal ingrowth of regenerating sensory axons. In the second study,we show that also human spinal cord neural stem/progenitor cells (hscNSPC) promote sensory axon ingrowth by the formation of a growth permissive tissue bridge that interferes with the spinal cord glial scar. Further, we tested whether this effect can be enhanced by combinatorial application of growth factors peptide mimetics. Interestingly, both hscNSPC and growth factor peptide mimetics alone but not in combination promote sensory regeneration. The observed failure of regeneration is likely caused by the reduced migration of hscNSPC when transplanted together with growth factor mimetics resulting in their inability to provide a continuous tissuebridge into the spinal cord. In the last study, we show first approaches to provide molecular tools that allow testing functional integration of stem cell derived neurons into the spinal cord.These tools are a prerequisite to test whether stem cells can also act as neuronal relays in the observed sensory regeneration events. In conclusion, this thesis provides first evidence that sensory regeneration is possible after dorsal root avulsion injury. This can be achieved by transplantation of human stem cell derived neuronal cells and to a certain degree by growth factor peptide mimetics.

Place, publisher, year, edition, pages
Uppsala: Uppsala University, Department of Neuroscience, 2015
Keywords
Regenerative Neurobiology, Stem cells, Sensory regeneration, Spinal cord injury
National Category
Neurosciences
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-264580 (URN)
Presentation
2015-12-14, B/C8:302, Husargatan 3, Uppsala, 10:15 (English)
Supervisors
Available from: 2015-11-18 Created: 2015-10-15 Last updated: 2018-01-10Bibliographically approved
Hoeber, J., Trolle, C., König, N., Du, Z., Gallo, A., Hermans, E., . . . Kozlova, E. N. (2015). Human Embryonic Stem Cell-Derived Progenitors Assist Functional Sensory Axon Regeneration after Dorsal Root Avulsion Injury. Scientific Reports, 5, Article ID 10666.
Open this publication in new window or tab >>Human Embryonic Stem Cell-Derived Progenitors Assist Functional Sensory Axon Regeneration after Dorsal Root Avulsion Injury
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2015 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 10666Article in journal (Refereed) Published
Abstract [en]

Dorsal root avulsion results in permanent impairment of sensory functions due to disconnection between the peripheral and central nervous system. Improved strategies are therefore needed to reconnect injured sensory neurons with their spinal cord targets in order to achieve functional repair after brachial and lumbosacral plexus avulsion injuries. Here, we show that sensory functions can be restored in the adult mouse if avulsed sensory fibers are bridged with the spinal cord by human neural progenitor (hNP) transplants. Responses to peripheral mechanical sensory stimulation were significantly improved in transplanted animals. Transganglionic tracing showed host sensory axons only in the spinal cord dorsal horn of treated animals. Immunohistochemical analysis confirmed that sensory fibers had grown through the bridge and showed robust survival and differentiation of the transplants. Section of the repaired dorsal roots distal to the transplant completely abolished the behavioral improvement. This demonstrates that hNP transplants promote recovery of sensorimotor functions after dorsal root avulsion, and that these effects are mediated by spinal ingrowth of host sensory axons. These results provide a rationale for the development of novel stem cell-based strategies for functionally useful bridging of the peripheral and central nervous system.

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-251488 (URN)10.1038/srep10666 (DOI)000356063500001 ()26053681 (PubMedID)
Funder
Swedish Research Council, 5420, 20716
Available from: 2015-04-20 Created: 2015-04-20 Last updated: 2018-01-11Bibliographically approved
Hoeber, J. (2015). Sensory regeneration in dorsal root avulsion. Neural Regeneration Research, 10(11), 1739-1740
Open this publication in new window or tab >>Sensory regeneration in dorsal root avulsion
2015 (English)In: Neural Regeneration Research, ISSN 1673-5374, E-ISSN 1876-7958, Vol. 10, no 11, p. 1739-1740Article in journal (Refereed) Published
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-275487 (URN)10.4103/1673-5374.170296 (DOI)000367332800011 ()
Funder
Swedish Research Council, 5420Swedish Research Council, 20716Stiftelsen Olle Engkvist Byggmästare
Available from: 2016-02-04 Created: 2016-02-04 Last updated: 2017-11-30Bibliographically approved
Ahmed, S., Wittenmayer, N., Kremer, T., Hoeber, J., Kiran Akula, A., Urlaub, H., . . . Dresbach, T. (2013). Mover is a homomeric phospho-protein present on synaptic vesicles. PLoS ONE, 8(5), e63474
Open this publication in new window or tab >>Mover is a homomeric phospho-protein present on synaptic vesicles
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 5, p. e63474-Article in journal (Refereed) Published
Abstract [en]

With remarkably few exceptions, the molecules mediating synaptic vesicle exocytosis at active zones are structurally and functionally conserved between vertebrates and invertebrates. Mover was found in a yeast-2-hybrid assay using the vertebrate-specific active zone scaffolding protein bassoon as a bait. Peptides of Mover have been reported in proteomics screens for self-interacting proteins, phosphorylated proteins, and synaptic vesicle proteins, respectively. Here, we tested the predictions arising from these screens. Using flotation assays, carbonate stripping of peripheral membrane proteins, mass spectrometry, immunogold labelling of purified synaptic vesicles, and immuno-organelle isolation, we found that Mover is indeed a peripheral synaptic vesicle membrane protein. In addition, by generating an antibody against phosphorylated Mover and Western blot analysis of fractionated rat brain, we found that Mover is a bona fide phospho-protein. The localization of Mover to synaptic vesicles is phosphorylation dependent; treatment with a phosphatase caused Mover to dissociate from synaptic vesicles. A yeast-2-hybrid screen, co-immunoprecipitation and cell-based optical assays of homomerization revealed that Mover undergoes homophilic interaction, and regions within both the N- and C- terminus of the protein are required for this interaction. Deleting a region required for homomeric interaction abolished presynaptic targeting of recombinant Mover in cultured neurons. Together, these data prove that Mover is associated with synaptic vesicles, and implicate phosphorylation and multimerization in targeting of Mover to synaptic vesicles and presynaptic sites.

National Category
Cell Biology
Identifiers
urn:nbn:se:uu:diva-224163 (URN)10.1371/journal.pone.0063474 (DOI)23723986 (PubMedID)
Available from: 2014-05-05 Created: 2014-05-05 Last updated: 2017-12-05Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-5602-0850

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