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Vernersson-Lindahl, Emma
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Publikasjoner (6 av 6) Visa alla publikasjoner
Mucibabic, M., Steneberg, P., Lidh, E., Straseviciene, J., Ziolkowska, A., Dahl, U., . . . Edlund, H. (2020). alpha-Synuclein promotes IAPP fibril formation in vitro and beta-cell amyloid formation in vivo in mice. Scientific Reports, 10(1), Article ID 20438.
Åpne denne publikasjonen i ny fane eller vindu >>alpha-Synuclein promotes IAPP fibril formation in vitro and beta-cell amyloid formation in vivo in mice
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2020 (engelsk)Inngår i: Scientific Reports, E-ISSN 2045-2322, Vol. 10, nr 1, artikkel-id 20438Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Type 2 diabetes (T2D), alike Parkinson's disease (PD), belongs to the group of protein misfolding diseases (PMDs), which share aggregation of misfolded proteins as a hallmark. Although the major aggregating peptide in beta -cells of T2D patients is Islet Amyloid Polypeptide (IAPP), alpha-synuclein (alpha Syn), the aggregating peptide in substantia nigra neurons of PD patients, is expressed also in beta -cells. Here we show that alpha Syn, encoded by Snca, is a component of amyloid extracted from pancreas of transgenic mice overexpressing human IAPP (denoted hIAPPtg mice) and from islets of T2D individuals. Notably, alpha Syn dose-dependently promoted IAPP fibril formation in vitro and tail-vein injection of alpha Syn in hIAPPtg mice enhanced beta -cell amyloid formation in vivo whereas beta -cell amyloid formation was reduced in hIAPPtg mice on a Snca (-/-) background. Taken together, our findings provide evidence that alpha Syn and IAPP co-aggregate both in vitro and in vivo, suggesting a role for alpha Syn in beta -cell amyloid formation.

sted, utgiver, år, opplag, sider
Nature Publishing Group, 2020
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-178308 (URN)10.1038/s41598-020-77409-z (DOI)000596280500007 ()33235246 (PubMedID)2-s2.0-85096611352 (Scopus ID)
Tilgjengelig fra: 2021-01-11 Laget: 2021-01-11 Sist oppdatert: 2024-07-02bibliografisk kontrollert
Steneberg, P., Lindahl, E., Dahl, U., Lidh, E., Straseviciene, J., Backlund, F., . . . Edlund, H. (2018). PAN-AMPK activator O304 improves glucose homeostasis and microvascular perfusion in mice and type 2 diabetes patients. JCI INSIGHT, 3(12), Article ID e99114.
Åpne denne publikasjonen i ny fane eller vindu >>PAN-AMPK activator O304 improves glucose homeostasis and microvascular perfusion in mice and type 2 diabetes patients
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2018 (engelsk)Inngår i: JCI INSIGHT, ISSN 2379-3708, Vol. 3, nr 12, artikkel-id e99114Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

AMPK activated protein kinase (AMPK), a master regulator of energy homeostasis, is activated in response to an energy shortage imposed by physical activity and caloric restriction. We here report on the identification of PAN-AMPK activator O304, which - in diet-induced obese mice - increased glucose uptake in skeletal muscle, reduced beta cell stress, and promoted beta cell rest. Accordingly, O304 reduced fasting plasma glucose levels and homeostasis model assessment of insulin resistance (HOMA-IR) in a proof-of-concept phase IIa clinical trial in type 2 diabetes (T2D) patients on Metformin. T2D is associated with devastating micro-and macrovascular complications, and O304 improved peripheral microvascular perfusion and reduced blood pressure both in animals and T2D patients. Moreover, like exercise, O304 activated AMPK in the heart, increased cardiac glucose uptake, reduced cardiac glycogen levels, and improved left ventricular stroke volume in mice, but it did not increase heart weight in mice or rats. Thus, O304 exhibits a great potential as a novel drug to treat T2D and associated cardiovascular complications.

sted, utgiver, år, opplag, sider
American Society for Clinical Investigation, 2018
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-150778 (URN)10.1172/jci.insight.99114 (DOI)000436144100013 ()29925691 (PubMedID)2-s2.0-85061843820 (Scopus ID)
Tilgjengelig fra: 2018-08-31 Laget: 2018-08-31 Sist oppdatert: 2024-07-02bibliografisk kontrollert
Sharma, S. K., Chorell, E., Steneberg, P., Vernersson-Lindahl, E., Edlund, H. & Wittung-Stafshede, P. (2015). Insulin-degrading enzyme prevents alpha-synuclein fibril formation in a nonproteolytical manner. Scientific Reports, 5, Article ID 12531.
Åpne denne publikasjonen i ny fane eller vindu >>Insulin-degrading enzyme prevents alpha-synuclein fibril formation in a nonproteolytical manner
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2015 (engelsk)Inngår i: Scientific Reports, E-ISSN 2045-2322, Vol. 5, artikkel-id 12531Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The insulin-degrading enzyme (IDE) degrades amyloidogenic proteins such as Amyloid β (Aβ) and Islet Amyloid Polypeptide (IAPP), i.e. peptides associated with Alzheimer's disease and type 2 diabetes, respectively. In addition to the protease activity normally associated with IDE function an additional activity involving the formation of stable, irreversible complexes with both Aβ and α-synuclein, an amyloidogenic protein involved in Parkinson's disease, was recently proposed. Here, we have investigated the functional consequences of IDE-α-synuclein interactions in vitro. We demonstrate that IDE in a nonproteolytic manner and at sub-stoichiometric ratios efficiently inhibits α-synuclein fibril formation by binding to α-synuclein oligomers making them inert to amyloid formation. Moreover, we show that, within a defined range of α-synuclein concentrations, interaction with α-synuclein oligomers increases IDE's proteolytic activity on a fluorogenic substrate. We propose that the outcomes of IDE-α-synuclein interactions, i.e. protection against α-synuclein amyloid formation and stimulated IDE protease activity, may be protective in vivo.

sted, utgiver, år, opplag, sider
Nature Publishing Group, 2015
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-107289 (URN)10.1038/srep12531 (DOI)000358773300001 ()26228656 (PubMedID)2-s2.0-84938523810 (Scopus ID)
Tilgjengelig fra: 2015-08-31 Laget: 2015-08-21 Sist oppdatert: 2024-07-02bibliografisk kontrollert
Witek, B., El Wakil, A., Nord, C., Ahlgren, U., Eriksson, M., Vernersson-Lindahl, E., . . . Palmer, R. H. (2015). Targeted Disruption of ALK Reveals a Potential Role in Hypogonadotropic Hypogonadism. PLOS ONE, 10(5), Article ID e0123542.
Åpne denne publikasjonen i ny fane eller vindu >>Targeted Disruption of ALK Reveals a Potential Role in Hypogonadotropic Hypogonadism
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2015 (engelsk)Inngår i: PLOS ONE, E-ISSN 1932-6203, Vol. 10, nr 5, artikkel-id e0123542Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Mice lacking ALK activity have previously been reported to exhibit subtle behavioral phenotypes. In this study of ALK of loss of function mice we present data supporting a role for ALK in hypogonadotropic hypogonadism in male mice. We observed lower level of serum testosterone at P40 in ALK knock-out males, accompanied by mild disorganization of seminiferous tubules exhibiting decreased numbers of GATA4 expressing cells. These observations highlight a role for ALK in testis function and are further supported by experiments in which chemical inhibition of ALK activity with the ALK TKI crizotinib was employed. Oral administration of crizotinib resulted in a decrease of serum testosterone levels in adult wild type male mice, which reverted to normal levels after cessation of treatment. Analysis of GnRH expression in neurons of the hypothalamus revealed a significant decrease in the number of GnRH positive neurons in ALK knock-out mice at P40 when compared with control littermates. Thus, ALK appears to be involved in hypogonadotropic hypogonadism by regulating the timing of pubertal onset and testis function at the upper levels of the hypothalamic-pituitary gonadal axis.

HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-106607 (URN)10.1371/journal.pone.0123542 (DOI)000356768100016 ()25955180 (PubMedID)2-s2.0-84949986427 (Scopus ID)
Tilgjengelig fra: 2015-07-28 Laget: 2015-07-24 Sist oppdatert: 2023-03-24bibliografisk kontrollert
Yang, H.-L., Eriksson, T., Vernersson, E., Vigny, M., Hallberg, B. & Palmer, R. (2007). The ligand Jelly Belly (Jeb) activates the Drosophila Alk RTK to drive PC12 cell differentiation, but is unable to activate the mouse ALK RTK. Journal of experimental zoology, part B Molecular and developmental evolution, 308(3), 269-282
Åpne denne publikasjonen i ny fane eller vindu >>The ligand Jelly Belly (Jeb) activates the Drosophila Alk RTK to drive PC12 cell differentiation, but is unable to activate the mouse ALK RTK
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2007 (engelsk)Inngår i: Journal of experimental zoology, part B Molecular and developmental evolution, ISSN 1552-5007, Vol. 308, nr 3, s. 269-282Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The Drosophila Alk receptor tyrosine kinase (RTK) drives founder cell specification in the developing visceral mesoderm and is crucial for the formation of the fly gut. Activation of Alk occurs in response to the secreted ligand Jelly Belly. No homologues of Jelly Belly are described in vertebrates, therefore we have approached the question of the evolutionary conservation of the Jeb-Alk interaction by asking whether vertebrate ALK is able to function in Drosophila. Here we show that the mouse ALK RTK is unable to rescue a Drosophila Alk mutant, indicating that mouse ALK is unable to recognise and respond to the Drosophila Jeb molecule. Furthermore, the overexpression of a dominant-negative Drosophila Alk transgene is able to block the visceral muscle fusion event, which an identically designed dominant-negative construct for the mouse ALK is not. Using PC12 cells as a model for neurite outgrowth, we show here for the first time that activation of dAlk by Jeb results in neurite extension. However, the mouse Alk receptor is unable to respond in any way to the Drosophila Jeb protein in the PC12 system. In conclusion, we find that the mammalian ALK receptor is unable to respond to the Jeb ligand in vivo or in vitro. These results suggest that either (i) mouse ALK and mouse Jeb have co-evolved to the extent that mALK can no longer recognise the Drosophila Jeb ligand or (ii) that the mALK RTK has evolved such that it is no longer activated by a Jeb-like molecule in vertebrates.

HSV kategori
Forskningsprogram
molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-17925 (URN)10.1002/jez.b.21146 (DOI)17285636 (PubMedID)2-s2.0-34249816481 (Scopus ID)
Tilgjengelig fra: 2008-01-10 Laget: 2008-01-10 Sist oppdatert: 2023-03-23bibliografisk kontrollert
Vernersson, E., Khoo, N. K., Henriksson, M., Roos, G., Palmer, R. & Hallberg, B. (2006). Characterization of the expression of the ALK receptor tyrosine kinase in mice.. Gene Expression Patterns, 6(5), 448-461
Åpne denne publikasjonen i ny fane eller vindu >>Characterization of the expression of the ALK receptor tyrosine kinase in mice.
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2006 (engelsk)Inngår i: Gene Expression Patterns, ISSN 1567-133X, E-ISSN 1872-7298, Vol. 6, nr 5, s. 448-461Artikkel i tidsskrift (Fagfellevurdert) Published
Emneord
Animals, Antibody Specificity, Base Sequence, DNA Primers, Gene Expression Regulation; Developmental, Immunohistochemistry, In Situ Hybridization, Mice, Protein-Tyrosine Kinases/*genetics/immunology/metabolism, RNA; Messenger/genetics/metabolism
Identifikatorer
urn:nbn:se:umu:diva-15366 (URN)10.1016/j.modgep.2005.11.006 (DOI)16458083 (PubMedID)2-s2.0-33744932431 (Scopus ID)
Tilgjengelig fra: 2008-01-11 Laget: 2008-01-11 Sist oppdatert: 2023-03-24bibliografisk kontrollert
Organisasjoner