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Wootz, Hanna
Publications (10 of 11) Show all publications
Wootz, H., FitzSimons-Kantamneni, E., Larhammar, M., Rotterman, T. M., Enjin, A., Patra, K., . . . Alvarez, F. J. (2013). Alterations in the motor neuron-renshaw cell circuit in the Sod1(G93A) mouse model. Journal of Comparative Neurology, 521(7), 1449-1469
Open this publication in new window or tab >>Alterations in the motor neuron-renshaw cell circuit in the Sod1(G93A) mouse model
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2013 (English)In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 521, no 7, p. 1449-1469Article in journal (Refereed) Published
Abstract [en]

Motor neurons become hyperexcitable during progression of amyotrophic lateral sclerosis (ALS). This abnormal firing behavior has been explained by changes in their membrane properties, but more recently it has been suggested that changes in premotor circuits may also contribute to this abnormal activity. The specific circuits that may be altered during development of ALS have not been investigated. Here we examined the Renshaw cell recurrent circuit that exerts inhibitory feedback control on motor neuron firing. Using two markers for Renshaw cells (calbindin and cholinergic nicotinic receptor subunit alpha2 [Chrna2]), two general markers for motor neurons (NeuN and vesicular acethylcholine transporter [VAChT]), and two markers for fast motor neurons (Chondrolectin and calcitonin-related polypeptide alpha [Calca]), we analyzed the survival and connectivity of these cells during disease progression in the Sod1G93A mouse model. Most calbindin-immunoreactive (IR) Renshaw cells survive to end stage but downregulate postsynaptic Chrna2 in presymptomatic animals. In motor neurons, some markers are downregulated early (NeuN, VAChT, Chondrolectin) and others at end stage (Calca). Early downregulation of presynaptic VAChT and Chrna2 was correlated with disconnection from Renshaw cells as well as major structural abnormalities of motor axon synapses inside the spinal cord. Renshaw cell synapses on motor neurons underwent more complex changes, including transitional sprouting preferentially over remaining NeuN-IR motor neurons. We conclude that the loss of presynaptic motor axon input on Renshaw cells occurs at early stages of ALS and disconnects the recurrent inhibitory circuit, presumably resulting in diminished control of motor neuron firing.

Keywords
amyotrophic lateral sclerosis, recurrent inhibition, VAChT, synapses
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-198594 (URN)10.1002/cne.23266 (DOI)000316421900001 ()
Available from: 2013-04-23 Created: 2013-04-22 Last updated: 2017-12-06Bibliographically approved
Andersson, L. S., Larhammar, M., Memic, F., Wootz, H., Schwochow, D., Rubin, C.-J., . . . Kullander, K. (2012). Mutations in DMRT3 affect locomotion in horses and spinal circuit function in mice. Nature, 488(7413), 642-646
Open this publication in new window or tab >>Mutations in DMRT3 affect locomotion in horses and spinal circuit function in mice
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2012 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 488, no 7413, p. 642-646Article in journal (Refereed) Published
Abstract [en]

Locomotion in mammals relies on a central pattern-generating circuitry of spinal interneurons established during development that coordinates limb movement(1). These networks produce left-right alternation of limbs as well as coordinated activation of flexor and extensor muscles(2). Here we show that a premature stop codon in the DMRT3 gene has a major effect on the pattern of locomotion in horses. The mutation is permissive for the ability to perform alternate gaits and has a favourable effect on harness racing performance. Examination of wild-type and Dmrt3-null mice demonstrates that Dmrt3 is expressed in the dI6 subdivision of spinal cord neurons, takes part in neuronal specification within this subdivision, and is critical for the normal development of a coordinated locomotor network controlling limb movements. Our discovery positions Dmrt3 in a pivotal role for configuring the spinal circuits controlling stride in vertebrates. The DMRT3 mutation has had a major effect on the diversification of the domestic horse, as the altered gait characteristics of a number of breeds apparently require this mutation.

National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-181404 (URN)10.1038/nature11399 (DOI)000308095100053 ()
Available from: 2012-09-28 Created: 2012-09-24 Last updated: 2017-12-07Bibliographically approved
Wallén-Mackenzie, Å., Wootz, H. & Englund, H. (2010). Genetic inactivation of the vesicular glutamate transporter 2 (VGLUT2) in the mouse: what have we learnt about functional glutamatergic neurotransmission?. Upsala Journal of Medical Sciences, 115(1), 11-20
Open this publication in new window or tab >>Genetic inactivation of the vesicular glutamate transporter 2 (VGLUT2) in the mouse: what have we learnt about functional glutamatergic neurotransmission?
2010 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 115, no 1, p. 11-20Article, review/survey (Refereed) Published
Abstract [en]

During the past decade, three proteins that possess the capability of packaging glutamate into presynaptic vesicles have been identified and characterized. These three vesicular glutamate transporters, VGLUT1-3, are encoded by solute carrier genes Slc17a6-8. VGLUT1 (Slc17a7) and VGLUT2 (Slc17a6) are expressed in glutamatergic neurons, while VGLUT3 (Slc17a8) is expressed in neurons classically defined by their use of another transmitter, such as acetylcholine and serotonin. As glutamate is both a ubiquitous amino acid and the most abundant neurotransmitter in the adult central nervous system, the discovery of the VGLUTs made it possible for the first time to identify and specifically target glutamatergic neurons. By molecular cloning techniques, different VGLUT isoforms have been genetically targeted in mice, creating models with alterations in their glutamatergic signalling. Glutamate signalling is essential for life, and its excitatory function is involved in almost every neuronal circuit. The importance of glutamatergic signalling was very obvious when studying full knockout models of both VGLUT1 and VGLUT2, none of which were compatible with normal life. While VGLUT1 full knockout mice die after weaning, VGLUT2 full knockout mice die immediately after birth. Many neurological diseases have been associated with altered glutamatergic signalling in different brain regions, which is why conditional knockout mice with abolished VGLUT-mediated signalling only in specific circuits may prove helpful in understanding molecular mechanisms behind such pathologies. We review the recent studies in which mouse genetics have been used to characterize the functional role of VGLUT2 in the central nervous system.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-138386 (URN)10.3109/03009730903572073 (DOI)000275061700003 ()
Available from: 2010-12-17 Created: 2010-12-17 Last updated: 2017-12-11Bibliographically approved
Wootz, H., Enjin, A., Wallen-Mackenzie, Å., Lindholm, D. & Kullander, K. (2010). Reduced VGLUT2 expression increases motor neuron viability in Sod1(G93A) mice. Neurobiology of Disease, 37(1), 58-66
Open this publication in new window or tab >>Reduced VGLUT2 expression increases motor neuron viability in Sod1(G93A) mice
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2010 (English)In: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 37, no 1, p. 58-66Article in journal (Refereed) Published
Abstract [en]

Glutamate-induced excitotoxicity has been suggested to influence pathogenesis in amyotrophic lateral sclerosis (ALS). Vesicular glutamate transporters (VGLUTs) are responsible for transport of glutamate into synaptic vesicles. Nerve terminals that envelop motor neurons in the spinal cord contain VGLUT2 and are likely responsible for most glutamate release on motor neurons. The role of VGLUT2 in ALS and its potential role to influence motor neuron survival have not previously been studied. Here, in a mouse model of ALS. we show that genetic reduction of VGLUT2 protein levels rescues motor neurons in the lumbar spinal cord and in the brainstem as well as neuromuscular junctions in tibialis anterior. Although the number of remaining motor neurons increased. neither disease onset nor life span was affected. We also show that the motor neuron subpopulation-specific markers calcitonin/calcitonin-related polypeptide alpha (Calca) and estrogen related receptor beta (ERR beta) respond in a similar way to reduced VGLUT2 as the whole motor neuron population suggesting that the rescued motor neurons are not of a particular motor unit type. Taken together, this suggests that reduced levels of VGLUT2 decrease motor neuron degeneration but do not prevent loss of motor neuron function in the SOD1(G93A) mouse model for ALS. (C) 2009 Elsevier Inc. All rights reserved

Keywords
ALS, Amyotrophic lateral sclerosis, Glutamate, Vglut2, Vesicular glutamate transporters, Excitotoxicity, Motor neuron, Neurodegeneration, Motor neuron subpopulations, Calca, Chondrolectin, Chodl, ERRb
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-127378 (URN)10.1016/j.nbd.2009.09.006 (DOI)000272533000008 ()
Available from: 2010-07-13 Created: 2010-07-13 Last updated: 2017-12-12Bibliographically approved
Wootz, H., Weber, E., Korhonen, L. & Lindholm, D. (2006). Altered distribution and levels of cathepsinD and cystatins in amyotrophic lateral sclerosis transgenic mice: Possible roles in motor neuron survival. Neuroscience, 143(2), 419-430
Open this publication in new window or tab >>Altered distribution and levels of cathepsinD and cystatins in amyotrophic lateral sclerosis transgenic mice: Possible roles in motor neuron survival
2006 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 143, no 2, p. 419-430Article in journal (Refereed) Published
Abstract [en]

In amyotrophic lateral sclerosis (ALS) there is a selective degeneration of motor neurons leading to muscle paralysis and death. The mechanism underlying cell demise in ALS is not fully understood, but involves the activation of different proteolytic enzymes, including the caspase family of cysteine proteases. We have here studied whether other proteases, such as the cathepsins, residing in lysosomes, and the cathepsin inhibitors, cystatinB and -C are changed in ALS. The expression and protein levels of the cathepsinB, -L and -D all increased in the spinal cord in ALS mice, carrying the mutant copper/zinc superoxide dismutase (SOD1) gene. At the cellular level, cathepsinB and -L were present in ventral motor neurons in controls, but in the ALS mice cathepsinB was also expressed by glial fibrillary acidic protein (GFAP) positive astrocytes. The distribution of the aspartic protease, cathepsinD also changed in ALS with a loss of the lysosomal staining in motor neurons. Inhibition of caspases by means of X-chromosome-linked inhibitor of apoptosis protein (XIAP) overexpression did not inhibit cleavage of cathepsinD in ALS mice, suggesting a caspase-independent pathway. Expression of cystatinB and -C increased slightly in the ALS spinal cords. Immunostaining showed that in ALS, cystatinC was present in motor neurons and in GFAP positive astrocytes. CystatinB that is a neuroprotective factor decreased in motor neurons in ALS but was expressed by activated microglial cells. The observed changes in the levels and distributions of cathepsinD and cystatinB and-C indicate a role of these proteins in the degeneration of motor neurons in ALS.

Keywords
nerve cell death, cathepsinD, cystatinB, cystatinC, microglia, ALS
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-95178 (URN)10.1016/j.neuroscience.2006.07.048 (DOI)000242351100006 ()16973300 (PubMedID)
Available from: 2006-11-24 Created: 2006-11-24 Last updated: 2017-12-14Bibliographically approved
Lindholm, D., Wootz, H. & Korhonen, L. (2006). ER stress and neurodegenerative diseases.. Cell Death Differ, 13(3), 385-92
Open this publication in new window or tab >>ER stress and neurodegenerative diseases.
2006 (English)In: Cell Death Differ, ISSN 1350-9047, Vol. 13, no 3, p. 385-92Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-76140 (URN)16397584 (PubMedID)
Available from: 2006-02-26 Created: 2006-02-26 Last updated: 2011-01-11
Ammoun, S., Lindholm, D., Wootz, H., Åkerman, K. E. O. & Kukkonen, J. P. (2006). G-protein-coupled OX1 Orexin/hcrtr-1 Hypocretin Receptors Induce Caspase-dependent and -independent Cell Death through p38 Mitogen-/Stress-activated Protein Kinase. Journal of Biological Chemistry, 281, 834-842
Open this publication in new window or tab >>G-protein-coupled OX1 Orexin/hcrtr-1 Hypocretin Receptors Induce Caspase-dependent and -independent Cell Death through p38 Mitogen-/Stress-activated Protein Kinase
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2006 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 281, p. 834-842Article in journal (Refereed) Published
Abstract [en]

We have investigated the signaling of OX1 receptors to cell death using Chinese hamster ovary cells as a model system. OX1 receptor stimulation with orexin-A caused a delayed cell death independently of cytosolic Ca2+ elevation. The classical mitogen-activated protein kinase (MAPK) pathways, ERK and p38, were strongly activated by orexin-A. p38 was essential for induction of cell death, whereas the ERK pathway appeared protective. A pathway often implicated in the p38-mediated cell death, activation of p53, did not mediate the cell death, as there was no stabilization of p53 or increase in p53-dependent transcriptional activity, and dominant-negative p53 constructs did not inhibit cell demise. Under basal conditions, orexin-A-induced cell death was associated with compact chromatin condensation and it required de novo gene transcription and protein synthesis, the classical hallmarks of programmed (apoptotic) cell death. However, though the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-(O-methyl)fluoromethyl ketone (Z-VAD-fmk) fully inhibited the caspase activity, it did not rescue the cells from orexin-A-induced death. In the presence of Z-VAD-fmk, orexin-A-induced cell death was still dependent on p38 and de novo protein synthesis, but it no longer required gene transcription. Thus, caspase inhibition causes activation of alternative, gene transcription-independent death pathway. In summary, the present study points out mechanisms for orexin receptor-mediated cell death and adds to our general understanding of the role of G-protein-coupled receptor signaling in cell death by suggesting a pathway from G-protein-coupled receptors to cell death via p38 mitogen-/stress-activated protein kinase independent of p53 and caspase activation.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-93310 (URN)10.1074/jbc.M508603200 (DOI)
Available from: 2005-09-01 Created: 2005-09-01 Last updated: 2017-12-14Bibliographically approved
Wootz, H., Hansson, I., Korhonen, L. & Lindholm, D. (2006). XIAP decreases caspase-12 cleavage and calpain activity in spinal cord of ALS. Exp Cell Res
Open this publication in new window or tab >>XIAP decreases caspase-12 cleavage and calpain activity in spinal cord of ALS
2006 (English)In: Exp Cell Res, ISSN 0014-4827Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-79030 (URN)16566922 (PubMedID)
Available from: 2006-04-03 Created: 2006-04-03 Last updated: 2011-01-11
Wootz, H. (2005). Amyotrophic lateral sclerosis - a study in transgenic mice. (Licentiate dissertation). : Uppsala University, Uppsala
Open this publication in new window or tab >>Amyotrophic lateral sclerosis - a study in transgenic mice
2005 (English)Licentiate thesis, monograph (Other scientific)
Place, publisher, year, edition, pages
Uppsala University, Uppsala, 2005. p. 22
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-86379 (URN)
Available from: 2006-04-03 Created: 2006-04-03
Möller, C., Alfredsson, J., Engström, M., Wootz, H., Xiang, Z., Lennartsson, J., . . . Nilsson, G. (2005). Stem cell factor promotes mast cell survival via inactivation of FOXO3a-mediated transcriptional induction and MEK-regulated phosphorylation of the proapoptotic protein Bim.. Blood, 106(4), 1330-6
Open this publication in new window or tab >>Stem cell factor promotes mast cell survival via inactivation of FOXO3a-mediated transcriptional induction and MEK-regulated phosphorylation of the proapoptotic protein Bim.
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2005 (English)In: Blood, ISSN 0006-4971, Vol. 106, no 4, p. 1330-6Article in journal (Refereed) Published
Abstract [en]

Mast cells are found in tissues throughout the body where they play important roles in the regulation of inflammatory responses. One characteristic feature of mast cells is their longevity. Although it is well established that mast cell survival is dependent on stem cell factor (SCF), it has not been described how this process is regulated. Herein, we report that SCF promotes mast cell survival through inactivation of the Forkhead transcription factor FOXO3a (forkhead box, class O3A) and down-regulation and phosphorylation of its target Bim (Bcl-2 [B-cell lymphoma-2] interacting modulator of cell death), a Bcl-2 homology 3 (BH3)-only proapoptotic protein. SCF induced a rapid and transient phosphorylation of Akt (protein kinase B) and FOXO3a. SCF treatment prevented up-regulation of Bim protein expression and led to increased Bim phosphorylation. Bim phosphorylation was inhibited by PD98059 and LY294002 treatment, suggesting the involvement of mitogen-activated protein kinase kinase/mitogen-activated protein kinase (MEK/MAPK) and phosphatidylinositol 3 (PI3)-kinase pathways in this process. Overexpression of phosphorylation-deficient FOXO3a caused an up-regulation of Bim and induced mast cell apoptosis even in the presence of SCF. Mast cell apoptosis induced by the phosphorylation-deficient FOXO3a was attenuated in bim-/- mast cells. Because apoptosis is abnormally reduced in bim-/- mast cells, these data provide evidence that Akt-mediated inhibition of FOXO3a and its transcription target Bim provides an important mechanism by which SCF acts to prevent apoptosis in mast cells.

Identifiers
urn:nbn:se:uu:diva-74139 (URN)15855272 (PubMedID)
Available from: 2005-08-31 Created: 2005-08-31 Last updated: 2011-01-11
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