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Lindholm, Dan
Publications (10 of 30) Show all publications
Peitsaro, N., Polianskyte, Z., Tuimala, J., Pörn-Ares, I., Liobikas, J., Speer, O., . . . Eriksson, O. (2008). Evolution of a family of metazoan active-site-serine enzymes from penicillin-binding proteins: a novel facet of the bacterial legacy.. BMC Evol Biol, 8, 26.
Open this publication in new window or tab >>Evolution of a family of metazoan active-site-serine enzymes from penicillin-binding proteins: a novel facet of the bacterial legacy.
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2008 (English)In: BMC Evol Biol, ISSN 1471-2148, Vol. 8, 26- p.Article in journal (Refereed) Published
Keyword
Amino Acid Sequence, Animals, Bacteria/enzymology/*genetics/metabolism, Binding Sites, Catalytic Domain, Conserved Sequence, Evolution; Molecular, Humans, Membrane Proteins/genetics, Molecular Weight, Penicillin-Binding Proteins/*metabolism, Ribosomal Proteins/genetics, Sequence Alignment, Sequence Homology, beta-Lactamases/*metabolism
Identifiers
urn:nbn:se:uu:diva-16401 (URN)18226203 (PubMedID)
Available from: 2008-05-20 Created: 2008-05-20 Last updated: 2011-01-11
Reijonen, S., Putkonen, N., Nørremølle, A., Lindholm, D. & Korhonen, L. (2008). Inhibition of endoplasmic reticulum stress counteracts neuronal cell death and protein aggregation caused by N-terminal mutant huntingtin proteins. Experimental Cell Research, 314(5), 950-960.
Open this publication in new window or tab >>Inhibition of endoplasmic reticulum stress counteracts neuronal cell death and protein aggregation caused by N-terminal mutant huntingtin proteins
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2008 (English)In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 314, no 5, 950-960 p.Article in journal (Refereed) Published
Abstract [en]

Accumulation of abnormal proteins occurs in many neuro degenerative diseases including Huntington's disease (HD). However, the precise role of protein aggregation in neuronal cell death remains unclear. We show here that the expression of N-terminal huntingtin proteins with expanded polyglutamine (polyQ) repeats causes cell death in neuronal PC6.3 cell that involves endoplasmic reticulum (ER) stress. These mutant huntingtin fragment proteins elevated Bip, an ER chaperone, and increased Chop and the phosphorylation of c-jun-N-terminal kinase (JNK) that are involved in cell death regulation. Caspase-12, residing in the ER, was cleaved in mutant huntingtin expressing cells, as was caspase-3 mediating cell death. In contrast, cytochrome-c or apoptosis inducing factor (AIF) was not released from mitochondria after the expression of these proteins. Treatment with salubrinal that inhibits ER stress counteracted cell death and reduced protein aggregations in the PC6.3 cells caused by the mutant huntingtin fragment proteins. Salubrinal upregulated Bip, reduced cleavage of caspase-12 and increased the phosphorylation of eukaryotic translation initiation factor-2 subunit-alpha (eIF2 alpha) that are neuroprotective. These results show that N-terminal mutant huntingtin proteins activate cellular pathways linked to ER stress, and that inhibition of ER stress by salubrinal increases cell survival. The data suggests that compounds targeting ER stress may be considered in designing novel approaches for treatment of HD and possibly other polyQ diseases.

Keyword
Huntington's disease, PC6.3 cell, endoplasmic reticulum stress, caspase, salubrinal, cell death
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-16400 (URN)10.1016/j.yexcr.2007.12.025 (DOI)000253752300002 ()18255062 (PubMedID)
Available from: 2008-05-20 Created: 2008-05-20 Last updated: 2017-12-08Bibliographically approved
Sokka, A.-L., Putkonen, N., Mudo, G., Pryazhnikov, E., Reijonen, S., Khiroug, L., . . . Korhonen, L. (2007). Endoplasmic Reticulum Stress Inhibition Protects against Excitotoxic Neuronal Injury in the Rat Brain. Journal of Neuroscience, 27(4), 901-908.
Open this publication in new window or tab >>Endoplasmic Reticulum Stress Inhibition Protects against Excitotoxic Neuronal Injury in the Rat Brain
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2007 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 27, no 4, 901-908 p.Article in journal (Refereed) Published
Abstract [en]

Elevated brain glutamate with activation of neuronal glutamate receptors accompanies neurological disorders, such as epilepsy and brain trauma. However, the mechanisms by which excitotoxicity triggers neuronal injury are not fully understood. We have studied the glutamate receptor agonist kainic acid (KA) inducing seizures and excitotoxic cell death. KA caused the disintegration of the endoplasmic reticulum (ER) membrane in hippocampal neurons and ER stress with the activation of the ER proteins Bip, Chop, and caspase-12. Salubrinal, inhibiting eIF2α (eukaryotic translation initiation factor 2 subunit α) dephosphorylation, significantly reduced KA-induced ERstress and neuronal death in vivo and in vitro. KA-induced rise in intracellular calcium was not affected by Salubrinal. The results show that ER responses are essential parts of excitotoxicity mediated by glutamate receptor activation and that Salubrinal decreases neuronal death in vivo. Inhibition of ER stress by small molecular compounds may be beneficial for treatment of various neuronal injuries and brain disorders.

Keyword
kainic acid, hippocampus, salubrinal, PERK, eIF2{alpha}, caspase-12
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-23434 (URN)10.1523/JNEUROSCI.4289-06.2007 (DOI)000243725200023 ()17251432 (PubMedID)
Available from: 2007-01-29 Created: 2007-01-29 Last updated: 2017-12-07Bibliographically approved
Bornhauser, B. C., Bonapace, L., Lindholm, D., Martinez, R., Cario, G., Schrappe, M., . . . Bourquin, J.-P. (2007). Low-dose arsenic trioxide sensitizes glucocorticoid-resistant acute lymphoblastic leukemia cells to dexamethasone via an Akt-dependent pathway. Blood, 110(6), 2084-2091.
Open this publication in new window or tab >>Low-dose arsenic trioxide sensitizes glucocorticoid-resistant acute lymphoblastic leukemia cells to dexamethasone via an Akt-dependent pathway
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2007 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 110, no 6, 2084-2091 p.Article in journal (Refereed) Published
Abstract [en]

Incorporation of apoptosis-inducing agents into current therapeutic regimens is an attractive strategy to improve treatment for drug-resistant leukemia. We tested the potential of arsenic trioxide (ATO) to restore the response to dexamethasone in glucocorticoid (GC)–resistant acute lymphoblastic leukemia (ALL). Low-dose ATO markedly increased in vitro GC sensitivity of ALL cells from T-cell and precursor B-cell ALL patients with poor in vivo response to prednisone. In GC-resistant cell lines, this effect was mediated, at least in part, by inhibition of Akt and affecting downstream Akt targets such as Bad, a proapoptotic Bcl-2 family member, and the X-linked inhibitor of apoptosis protein (XIAP). Combination of ATO and dexamethasone resulted in increased Bad and rapid down-regulation of XIAP, while levels of the antiapoptotic regulator Mcl-1 remained unchanged. Expression of dominant-active Akt, reduction of Bad expression by RNA interference, or overexpression of XIAP abrogated the sensitizing effect of ATO. The inhibitory effect of XIAP overexpression was reduced when the Akt phosphorylation site was mutated (XIAP-S87A). These data suggest that the combination of ATO and glucocorticoids could be advantageous in GC-resistant ALL and reveal additional targets for the evaluation of new antileukemic agents.

Keyword
Antineoplastic Agents/administration & dosage/*pharmacology, Apoptosis/drug effects, Arsenicals/*administration & dosage/pharmacology, Blotting; Western, Caspases, Cell Line; Tumor/drug effects, Cell Survival/drug effects, Dexamethasone/*pharmacology, Drug Resistance; Neoplasm, Drug Synergism, Glucocorticoids/*pharmacology, Humans, Neoplasm; Residual/diagnosis, Oxides/*administration & dosage/pharmacology, Phosphorylation/drug effects, Precursor Cell Lymphoblastic Leukemia-Lymphoma/*drug therapy/metabolism/pathology, Prednisone/pharmacology, Proto-Oncogene Proteins c-akt/*metabolism, RNA; Small Interfering/pharmacology, Reactive Oxygen Species/metabolism, Remission Induction, Signal Transduction, Sirolimus/pharmacology, Transfection, X-Linked Inhibitor of Apoptosis Protein/metabolism, bcl-Associated Death Protein/metabolism
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-12885 (URN)10.1182/blood-2006-12-060970 (DOI)000249671700056 ()17537996 (PubMedID)
Available from: 2008-01-18 Created: 2008-01-18 Last updated: 2017-12-11Bibliographically approved
Boström, M., Anderson, M., Lindholm, D., Park, K.-H., Schrott-Fischer, A., Pfaller, K., . . . Rask-Andersen, H. (2007). Neural network and "Ganglion" formations in vitro: a video microscopy and scanning electron microscopy study on adult cultured spiral ganglion cells.. Otology and Neurotology, 28(8), 1109-1119.
Open this publication in new window or tab >>Neural network and "Ganglion" formations in vitro: a video microscopy and scanning electron microscopy study on adult cultured spiral ganglion cells.
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2007 (English)In: Otology and Neurotology, ISSN 1531-7129, E-ISSN 1537-4505, Vol. 28, no 8, 1109-1119 p.Article in journal (Refereed) Published
Abstract [en]

Hypothesis: To analyze if adult-dissociated spiral ganglion cells may be propagated in vitro for later use in transplantation models to form integrated neural networks. Background: Hearing loss is often associated with primary or secondary spiral ganglion cell degeneration. New strategies for cell repair and tissue engineering warrants further elucidation of the regenerative capacity of the auditory nerve. Methods: We used in vitro/in video microscopy in combination with immunocytochemistry and field emission scanning electron microscopy to analyze neural development and network formation from dissociated adult guinea pig spiral ganglion cells. Cells were cultured in serum-free medium and in the presence of brain-derived neurotrophic factor, neurotrophin 3, and glia cell line-derived neurotrophic factor for up to 8 weeks. Results: Time-lapse video microscopy and scanning electron microscopy exposed the propagation of auditory neurons and the role of neural growth cones in axon locomotion, fasciculation, and nuclear migration, often ensuing in cell congregation (ganglion-like formations) during network formation. Axons were sometimes ensheathed by adjoining S-100/glia fibrillary acidic protein-expressing cells. A few expanding neurons were nestin positive and sometimes incorporated the markers of proliferating cells Ki67 and 5'-bromo-2-deoxyuridine. Neurons expressed the markers and transcription factors for neural development neurogenin 1, neurogenic differentiation factor 1, Brn3a, and GATA binding protein 3, as well as the neural markers beta-III tubulin, NeuN, and neurofilament 160 during this process. Conclusion: This method of culturing and expanding spiral ganglion neurons in vitro may be useful in further studies of cell transplantation models aiming to restore the injured inner ear.

Keyword
in vitro, neural network, SEM, spiral ganglion, time-lapse video microscopy
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-12880 (URN)10.1097/MAO.0b013e318159e710 (DOI)000251358900023 ()18043436 (PubMedID)
Available from: 2008-02-20 Created: 2008-02-20 Last updated: 2017-12-11Bibliographically approved
Zhu, C., Xu, F., Fukuda, A., Wang, X., Fukuda, H., Korhonen, L., . . . Blomgren, K. (2007). X chromosome-linked inhibitor of apoptosis protein reduces oxidative stress after cerebral irradiation or hypoxia-ischemia through up-regulation of mitochondrial antioxidants. European Journal of Neuroscience, 26(12), 3402-3410.
Open this publication in new window or tab >>X chromosome-linked inhibitor of apoptosis protein reduces oxidative stress after cerebral irradiation or hypoxia-ischemia through up-regulation of mitochondrial antioxidants
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2007 (English)In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 26, no 12, 3402-3410 p.Article in journal (Refereed) Published
Abstract [en]

We demonstrate that X chromosome-linked inhibitor of apoptosis protein (XIAP) counteracts oxidative stress in two essentially different disease-related models of brain injury, hypoxia-ischemia and irradiation, as judged by lower expression of nitrotyrosine (5-fold) and 4-hydroxy-2-nonenal (10-fold) in XIAP-overexpressing compared with wild-type mice. XIAP overexpression induced up-regulation of at least three antioxidants residing in mitochondria, superoxide dismutase 2, thioredoxin 2 and lysine oxoglutarate reductase. Cytochrome c release from mitochondria was reduced in XIAP-overexpressing mice. Hence, in addition to blocking caspases, XIAP can regulate reactive oxygen species in the brain, at least partly through up-regulation of mitochondrial antioxidants. XIAP-induced prevention of oxidative stress was not secondary to tissue protection because although XIAP overexpression provides tissue protection after hypoxia-ischemia, it does not prevent tissue loss after irradiation. This is a previously unknown role of XIAP and may provide the basis for development of novel protective strategies for both acute and chronic neurodegenerative diseases, where oxidative stress is an integral component of the injury mechanisms involved.

Keyword
irradiation, ischemia, superoxide dismutase, thioredoxin, mouse
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-12883 (URN)10.1111/j.1460-9568.2007.05948.x (DOI)000251552200007 ()18052985 (PubMedID)
Available from: 2008-01-18 Created: 2008-01-18 Last updated: 2017-12-11Bibliographically approved
Kairisalo, M., Korhonen, L., Blomgren, K. & Lindholm, D. (2007). X-linked inhibitor of apoptosis protein increases mitochondrial antioxidants through NF-kappaB activation. Biochemical and Biophysical Research Communications - BBRC, 364(1), 138-144.
Open this publication in new window or tab >>X-linked inhibitor of apoptosis protein increases mitochondrial antioxidants through NF-kappaB activation
2007 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 364, no 1, 138-144 p.Article in journal (Refereed) Published
Abstract [en]

X chromosome-linked inhibitor of apoptosis protein is an endogenous inhibitor of caspases and is an important regulator of cell death. XIAP can also influence cell signaling, but downstream proteins affected are largely unknown. We show here using neuronal PC6.3 cells that XIAP increases the levels of antioxidants, particularly superoxide dismutase-2 that is localized to mitochondria. Studies using reporter constructs and NF-κB Rel-A deficient mouse embryonic fibroblasts showed that NF-κB signaling is required for the induction of Sod2 by XIAP. XIAP also reduced oxidative stress in the PC6.3 cells as shown by decreased production of reactive oxygen species. These findings disclose a novel role for XIAP in control of oxidative stress and mitochondrial antioxidants that may contribute to cell protection after various injuries.

Keyword
Mitochondria, NF-κB, Oxidative stress, Sod2, XIAP
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-12878 (URN)10.1016/j.bbrc.2007.09.115 (DOI)000250661500022 ()17936246 (PubMedID)
Available from: 2008-01-18 Created: 2008-01-18 Last updated: 2017-12-11Bibliographically 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, 419-430 p.Article 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.

Keyword
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, 385-92 p.Article 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
Sundberg, M., Savola, S., Hienola, A., Korhonen, L. & Lindholm, D. (2006). Glucocorticoid hormones decrease proliferation of embryonic neural stem cells. J Neurosci, 26(20), 5402-10.
Open this publication in new window or tab >>Glucocorticoid hormones decrease proliferation of embryonic neural stem cells
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2006 (English)In: J Neurosci, ISSN 1529-2401, Vol. 26, no 20, 5402-10 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-80657 (URN)16707792 (PubMedID)
Available from: 2006-05-19 Created: 2006-05-19 Last updated: 2011-01-11
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