Publications by authors named "Dan Lindholm"

87 Publications

Sphingolipids as Modulators of SARS-CoV-2 Infection.

Front Cell Dev Biol 2021 17;9:689854. Epub 2021 Jun 17.

Minerva Foundation Institute for Medical Research, Helsinki, Finland.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 pandemic with severe consequences for afflicted individuals and the society as a whole. The biology and infectivity of the virus has been intensively studied in order to gain a better understanding of the molecular basis of virus-host cell interactions during infection. It is known that SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) via its spike protein. Priming of the virus by specific proteases leads to viral entry via endocytosis and to the subsequent steps in the life cycle of SARS-CoV-2. Sphingosine and ceramide belong to the sphingolipid family and are abundantly present in cell membranes. These lipids were recently shown to interfere with the uptake of virus particles of SARS-CoV-2 into epithelial cell lines and primary human nasal cells in culture. The mechanisms of action were partly different, as sphingosine blocked, whilst ceramide facilitated viral entry. Acid sphingomyelinase (ASM) is vital for the generation of ceramide and functional inhibition of ASM by drugs like amitriptyline reduced SARS-CoV-2 entry into the epithelial cells. Recent data indicates that serum level of sphingosine-1-phosphate (S1P) is a prognostic factor for COVID-2 severity. Further, stimulation of sphingosine-1-phosphate receptor 1 (S1PR1) might also constrain the hyper-inflammatory conditions linked to SARS-CoV-2. Here, we review recent exciting findings regarding sphingolipids in the uptake of SARS-CoV-2 and in the course of COVID-19 disease. More studies are required on the mechanisms of action and the potential use of antidepressant drugs and sphingolipid modifiers in SARS-CoV-2 infections and in the treatment of the more serious and fatal consequences of the disease.
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http://dx.doi.org/10.3389/fcell.2021.689854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245774PMC
June 2021

PGC-1α Signaling Increases GABA(A) Receptor Subunit α2 Expression, GABAergic Neurotransmission and Anxiety-Like Behavior in Mice.

Front Mol Neurosci 2021 1;14:588230. Epub 2021 Feb 1.

Medicum, Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland.

Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a master regulator of mitochondria biogenesis and cell stress playing a role in metabolic and degenerative diseases. In the brain PGC-1α expression has been localized mainly to GABAergic interneurons but its overall role is not fully understood. We observed here that the protein levels of γ-aminobutyric acid (GABA) type A receptor-α2 subunit (GABARα2) were increased in hippocampus and brain cortex in transgenic (Tg) mice overexpressing PGC-1α in neurons. Along with this, GABARα2 expression was enhanced in the hippocampus of the PGC-1α Tg mice, as shown by quantitative PCR. Double immunostaining revealed that GABARα2 co-localized with the synaptic protein gephyrin in higher amounts in the striatum radiatum layer of the hippocampal CA1 region in the Tg compared with Wt mice. Electrophysiology revealed that the frequency of spontaneous and miniature inhibitory postsynaptic currents (mIPSCs) was increased in the CA1 region in the Tg mice, indicative of an augmented GABAergic transmission. Behavioral tests revealed an increase for anxiety-like behavior in the PGC-1α Tg mice compared with controls. To study whether drugs acting on PPARγ can affect GABARα2, we employed pioglitazone that elevated GABARα2 expression in primary cultured neurons. Similar results were obtained using the specific PPARγ agonist, N-(2-benzoylphenyl)-O-[2-(methyl-2-pyridinylamino) ethyl]-L-tyrosine hydrate (GW1929). These results demonstrate that PGC-1α regulates GABARα2 subunits and GABAergic neurotransmission in the hippocampus with behavioral consequences. This indicates further that drugs like pioglitazone, widely used in the treatment of type 2 diabetes, can influence GABARα2 expression via the PPARγ/PGC-1α system.
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http://dx.doi.org/10.3389/fnmol.2021.588230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882546PMC
February 2021

The Unfolded Protein Response and Autophagy as Drug Targets in Neuropsychiatric Disorders.

Front Cell Neurosci 2020 29;14:554548. Epub 2020 Sep 29.

Medicum, Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

Neurons are polarized in structure with a cytoplasmic compartment extending into dendrites and a long axon that terminates at the synapse. The high level of compartmentalization imposes specific challenges for protein quality control in neurons making them vulnerable to disturbances that may lead to neurological dysfunctions including neuropsychiatric diseases. Synapse and dendrites undergo structural modulations regulated by neuronal activity involve key proteins requiring strict control of their turnover rates and degradation pathways. Recent advances in the study of the unfolded protein response (UPR) and autophagy processes have brought novel insights into the specific roles of these processes in neuronal physiology and synaptic signaling. In this review, we highlight recent data and concepts about UPR and autophagy in neuropsychiatric disorders and synaptic plasticity including a brief outline of possible therapeutic approaches to influence UPR and autophagy signaling in these diseases.
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http://dx.doi.org/10.3389/fncel.2020.554548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550790PMC
September 2020

Protective Role of Low Ethanol Administration Following Ischemic Stroke via Recovery of KCC2 and p75 Expression.

Mol Neurobiol 2021 Mar 24;58(3):1145-1161. Epub 2020 Oct 24.

Neuroscience Center-HiLIFE, University of Helsinki, 00014, Helsinki, Finland.

A striking result from epidemiological studies show a correlation between low alcohol intake and lower incidence for ischemic stroke and severity of derived brain injury. Although reduced apoptosis and inflammation has been suggested to be involved, little is known about the mechanism mediating this effect in vivo. Increase in intracellular chloride concentration and derived depolarizing GABAR-mediated transmission are common consequences following various brain injuries and are caused by the abnormal expression levels of the chloride cotransporters NKCC1 and KCC2. Downstream pro-apoptotic signaling through p75 may link GABA depolarization with post-injury neuronal apoptosis. Here, we show that changes in GABAergic signaling, Cl homeostasis, and expression of chloride cotransporters in the post-traumatic mouse brain can be significantly reduced by administration of 3% ethanol to the drinking water. Ethanol-induced upregulation of KCC2 has a positive impact on neuronal survival, preserving a large part of the cortical peri-infarct zone, as well as preventing the massive post-ischemic upregulation of the pro-apoptotic protein p75. Importantly, intracortical multisite in vivo recordings showed that ethanol treatment could significantly ameliorate stroke-induced reduction in cortical activity. This surprising finding discloses a pathway triggered by low concentration of ethanol as a novel therapeutically relevant target.
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http://dx.doi.org/10.1007/s12035-020-02176-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878264PMC
March 2021

Finnish neuroscience from past to present.

Eur J Neurosci 2020 09 18;52(5):3273-3289. Epub 2020 Feb 18.

Department of Pathology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

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http://dx.doi.org/10.1111/ejn.14693DOI Listing
September 2020

Dynamic Interaction of USP14 with the Chaperone HSC70 Mediates Crosstalk between the Proteasome, ER Signaling, and Autophagy.

iScience 2020 Jan 19;23(1):100790. Epub 2019 Dec 19.

Medicum, Department of Biochemistry and Developmental Biology, Faculty of MedicineUniversity of Helsinki, P.O. Box 63, FIN-00014 Helsinki, Finland; Minerva Foundation Institute for Medical Research, Biomedicum Helsinki 2U, Tukholmankatu 8, FIN-00290 Helsinki, Finland. Electronic address:

USP14 is a deubiquitinating enzyme associated with the proteasome important for protein degradation. Here we show that upon proteasome inhibition or expression of the mutant W58A-USP14, association of USP14 with the 19S regulatory particle is disrupted. MS-based interactomics revealed an interaction of USP14 with the chaperone, HSC70, in neuroblastoma cells. Proteasome inhibition enhanced binding of USP14 to HSC70, and to XBP1u and IRE1α proteins, demonstrating a role in the unfolded protein response. Striatal neurons expressing mutant huntingtin exhibited reduced USP14 and HSC70 levels, whereas inhibition of HSC70 downregulated USP14. Furthermore, proteasome inhibition or use of the mutant W58A-USP14 facilitated the interaction of USP14 with the autophagy protein, GABARAP. Functionally, overexpression of W58A-USP14 increased GABARAP positive autophagosomes in striatal neurons, and this was abrogated using the HSC70 inhibitor, VER-155008. Modulation of the USP14-HSC70 axis may represent a potential therapeutic target in HD to beneficially influence multiple proteostasis pathways.
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http://dx.doi.org/10.1016/j.isci.2019.100790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941875PMC
January 2020

Prolyl oligopeptidase inhibition reduces PolyQ aggregation and improves cell viability in cellular model of Huntington's disease.

J Cell Mol Med 2019 12 29;23(12):8511-8515. Epub 2019 Sep 29.

Division of Pharmacology and Pharmacotherapy, University of Helsinki, Helsinki, Finland.

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http://dx.doi.org/10.1111/jcmm.14675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850970PMC
December 2019

Caspase-2 and p75 neurotrophin receptor (p75NTR) are involved in the regulation of SREBP and lipid genes in hepatocyte cells.

Cell Death Dis 2019 07 11;10(7):537. Epub 2019 Jul 11.

Medicum, Department of Biochemistry and Developmental Biology, Medical Faculty, University of Helsinki, POB 63, FI-00014, Helsinki, Finland.

Lipid-induced toxicity is part of several human diseases, but the mechanisms involved are not fully understood. Fatty liver is characterized by the expression of different growth and tissue factors. The neurotrophin, nerve growth factor (NGF) and its pro-form, pro-NGF, are present in fatty liver together with p75 neurotrophin receptor (p75NTR). Stimulation of human Huh7 hepatocyte cells with NGF and pro-NGF induced Sterol-regulator-element-binding protein-2 (SREBP2) activation and increased Low-Density Lipoprotein Receptor (LDLR) expression. We observed that phosphorylation of caspase-2 by p38 MAPK was essential for this regulation involving a caspase-3-mediated cleavage of SREBP2. RNA sequencing showed that several genes involved in lipid metabolism were altered in p75NTR-deficient mouse liver. The same lipogenic genes were downregulated in p75NTR gene-engineered human Huh7 cells and reciprocally upregulated by stimulation of p75NTRs. In the knock-out mice the serum cholesterol and triglyceride levels were reduced, suggesting a physiological role of p75NTRs in whole-body lipid metabolism. Taken together, this study shows that p75NTR signaling influences a network of genes involved in lipid metabolism in liver and hepatocyte cells. Modulation of p75NTR signaling may be a target to consider in various metabolic disorders accompanied by increased lipid accumulation.
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http://dx.doi.org/10.1038/s41419-019-1758-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624261PMC
July 2019

The E3 ubiquitin ligase inducible degrader of the LDL receptor/myosin light chain interacting protein in health and disease.

Curr Opin Lipidol 2019 06;30(3):192-197

Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands.

Purpose Of Review: The RING E3 ubiquitin ligase inducible degrader of the LDL receptor (IDOL, also known as MYLIP) promotes ubiquitylation and subsequent lysosomal degradation of the LDL receptor (LDLR), thus acting to limit uptake of lipoprotein-derived cholesterol into cells. Next to the LDLR, IDOL also promotes degradation of two related receptors, the very LDL receptor (VLDLR) and apolipoprotein E receptor 2 (APOER2), which have important signaling functions in the brain. We review here the emerging role of IDOL in lipoprotein and energy metabolism, neurodegenerative diseases, and the potential for therapeutic targeting of IDOL.

Recent Findings: Genetic studies suggest an association between IDOL and lipoprotein metabolism in humans. Studies in rodents and nonhuman primates support an in-vivo role for IDOL in lipoprotein metabolism, and also uncovered an unexpected role in whole-body energy metabolism. Recent evaluation of IDOL function in the brain revealed a role in memory formation and progression of Alzheimer's disease. The report of the first IDOL inhibitor may facilitate further investigations on therapeutic strategies to target IDOL.

Summary: IDOL is emerging as an important determinant of lipid and energy metabolism in metabolic disease as well as in Alzheimer's disease. IDOL targeting may be beneficial in treating these conditions.
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http://dx.doi.org/10.1097/MOL.0000000000000593DOI Listing
June 2019

Lactate-Induced Glucose Output Is Unchanged by Metformin at a Therapeutic Concentration - A Mass Spectrometry Imaging Study of the Perfused Rat Liver.

Front Pharmacol 2018 22;9:141. Epub 2018 Feb 22.

Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

Metformin is the first line drug for type 2 diabetes but its molecular mechanisms remain unclear. Here, we have studied the acute effect of a therapeutically relevant intrahepatic concentration of metformin on glucose production from lactate. We selected the perfused rat liver as experimental system since it enables the complete control of drug dosage. We used MALDI (matrix-assisted laser desorption/ionization) mass spectrometry imaging to estimate the concentration of metformin in the livers and we measured the concentration of glucose in the effluent medium under basal conditions and following lactate addition. MALDI mass spectra of thin-sections of freeze-clamped rat liver perfused with metformin showed a peak at 130.16 which was unambiguously assigned to metformin. The mass spectrometric detection limit was at a tissue concentration of about 250 nM, and uptake of metformin from the perfusion medium to the liver occurred with a K of 0.44 mM. Metformin was evenly distributed in the liver irrespective of its concentration in the perfusion medium and the duration of a perfusion. At a parenchymal concentration of 30 μM, metformin did not induce any significant suppression of the basal or lactate-induced glucose release from the liver. These results show that matrix-assisted laser desorption/ionization mass spectrometry imaging can be applied to estimate the tissue concentration and distribution of metformin in a therapeutically relevant micromolar concentration range. Our findings challenge the view that metformin causes an inhibition of glucose release from the liver by an acute inhibition of mitochondrial glycerol 3-phosphate dehydrogenase (EC 1.1.5.3).
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http://dx.doi.org/10.3389/fphar.2018.00141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5827415PMC
February 2018

Prostaglandin D2 Receptor DP1 Antibodies Predict Vaccine-induced and Spontaneous Narcolepsy Type 1: Large-scale Study of Antibody Profiling.

EBioMedicine 2018 Mar 2;29:47-59. Epub 2018 Feb 2.

Protobios Llc, Mäealuse 4, 12618 Tallinn, Estonia; Department of Gene Technology, Tallinn University of Technology, Akadeemia Tee 15, 12618 Tallinn, Estonia. Electronic address:

Background: Neuropathological findings support an autoimmune etiology as an underlying factor for loss of orexin-producing neurons in spontaneous narcolepsy type 1 (narcolepsy with cataplexy; sNT1) as well as in Pandemrix influenza vaccine-induced narcolepsy type 1 (Pdmx-NT1). The precise molecular target or antigens for the immune response have, however, remained elusive.

Methods: Here we have performed a comprehensive antigenic repertoire analysis of sera using the next-generation phage display method - mimotope variation analysis (MVA). Samples from 64 children and adolescents were analyzed: 10 with Pdmx-NT1, 6 with sNT1, 16 Pandemrix-vaccinated, 16 H1N1 infected, and 16 unvaccinated healthy individuals. The diagnosis of NT1 was defined by the American Academy of Sleep Medicine international criteria of sleep disorders v3.

Findings: Our data showed that although the immunoprofiles toward vaccination were generally similar in study groups, there were also striking differences in immunoprofiles between sNT1 and Pdmx-NT1 groups as compared with controls. Prominent immune response was observed to a peptide epitope derived from prostaglandin D2 receptor (DP1), as well as peptides homologous to B cell lymphoma 6 protein. Further validation confirmed that these can act as true antigenic targets in discriminating NT1 diseased along with a novel epitope of hemagglutinin of H1N1 to delineate exposure to H1N1.

Interpretation: We propose that DP1 is a novel molecular target of autoimmune response and presents a potential diagnostic biomarker for NT1. DP1 is involved in the regulation of non-rapid eye movement (NREM) sleep and thus alterations in its functions could contribute to the disturbed sleep regulation in NT1 that warrants further studies. Together our results also show that MVA is a helpful method for finding novel peptide antigens to classify human autoimmune diseases, possibly facilitating the design of better therapies.
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http://dx.doi.org/10.1016/j.ebiom.2018.01.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5925455PMC
March 2018

Commentary: LACTB is a tumour suppressor that modulates lipid metabolism and cell state.

Front Physiol 2017 8;8:396. Epub 2017 Jun 8.

Biochemistry and Developmental Biology, Faculty of Medicine, University of HelsinkiHelsinki, Finland.

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http://dx.doi.org/10.3389/fphys.2017.00396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5462942PMC
June 2017

Orexin receptor agonist Yan 7874 is a weak agonist of orexin/hypocretin receptors and shows orexin receptor-independent cytotoxicity.

PLoS One 2017 2;12(6):e0178526. Epub 2017 Jun 2.

Biochemistry and Cell Biology, Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.

Two promising lead structures of small molecular orexin receptor agonist have been reported, but without detailed analyses of the pharmacological properties. One of them, 1-(3,4-dichlorophenyl)-2-[2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl]ethan-1-ol (Yan 7874), is commercially available, and we set out to analyze its properties. As test system we utilized human OX1 and OX2 orexin receptor-expressing Chinese hamster ovary (CHO) K1 cells as well as control CHO-K1 and neuro-2a neuroblastoma cells. Gq-coupling was assessed by measurement of intracellular Ca2+ and phospholipase C activity, and the coupling to Gi and Gs by adenylyl cyclase inhibition and stimulation, respectively. At concentrations above 1 μM, strong Ca2+ and low phospholipase C responses to Yan 7874 were observed in both OX1- and OX2-expressing cells. However, a major fraction of the response was not mediated by orexin receptors, as determined utilizing the non-selective orexin receptor antagonist N-biphenyl-2-yl-1-{[(1-methyl-1H-benzimidazol-2-yl)sulfanyl]acetyl}-L-prolinamide (TCS 1102) as well as control CHO-K1 cells. Yan 7874 did not produce any specific adenylyl cyclase response. Some experiments suggested an effect on cell viability by Yan 7874, and we thus analyzed this. Within a few hours of exposure, Yan 7874 markedly changed cell morphology (shrunken, rich in vacuoles), reduced growth, promoted cell detachment, and induced necrotic cell death. The effect was equal in cells expressing orexin receptors or not. Thus, Yan 7874 is a weak partial agonist of orexin receptors. It also displays strong off-target effects in the same concentration range, culminating in necrotic cell demise. This makes Yan 7874 unsuitable as orexin receptor agonist.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178526PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5456073PMC
October 2017

Recent Insights into the Role of Unfolded Protein Response in ER Stress in Health and Disease.

Front Cell Dev Biol 2017 10;5:48. Epub 2017 May 10.

Department of Pathophysiology, University of TartuTartu, Estonia.

Unfolded stress response (UPR) is a conserved cellular pathway involved in protein quality control to maintain homeostasis under different conditions and disease states characterized by cell stress. Although three general schemes of and genes induced by UPR are rather well-established, open questions remain including the precise role of UPR in human diseases and the interactions between different sensor systems during cell stress signaling. Particularly, the issue how the normally adaptive and pro-survival UPR pathway turns into a deleterious process causing sustained endoplasmic reticulum (ER) stress and cell death requires more studies. UPR is also named a friend with multiple personalities that we need to understand better to fully recognize its role in normal physiology and in disease pathology. UPR interacts with other organelles including mitochondria, and with cell stress signals and degradation pathways such as autophagy and the ubiquitin proteasome system. Here we review current concepts and mechanisms of UPR as studied in different cells and model systems and highlight the relevance of UPR and related stress signals in various human diseases.
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http://dx.doi.org/10.3389/fcell.2017.00048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5423914PMC
May 2017

XIAP Interacts with and Regulates the Activity of FAF1.

Biochim Biophys Acta Mol Cell Res 2017 Jul 13;1864(7):1335-1348. Epub 2017 Apr 13.

Molecular Neuroprotection Laboratory, Hospital Nacional de Parapléjicos, SESCAM, Toledo, Spain. Electronic address:

Cell death depends on the balance between the activities of pro- and anti-apoptotic factors. X-linked inhibitor of apoptosis protein (XIAP) plays an important role in the cytoprotective process by inhibiting the caspase cascade and regulating pro-survival signaling pathways. While searching for novel interacting partners of XIAP, we identified Fas-associated factor 1 (FAF1). Contrary to XIAP, FAF1 is a pro-apoptotic factor that also regulates several signaling pathways in which XIAP is involved. However, the functional relationship between FAF1 and XIAP is unknown. Here, we describe a new interaction between XIAP and FAF1 and describe the functional implications of their opposing roles in cell death and NF-κB signaling. Our results clearly demonstrate the interaction of XIAP with FAF1 and define the specific region of the interaction. We observed that XIAP is able to block FAF1-mediated cell death by interfering with the caspase cascade and directly interferes in NF-κB pathway inhibition by FAF1. Furthermore, we show that XIAP promotes ubiquitination of FAF1. Conversely, FAF1 does not interfere with the anti-apoptotic activity of XIAP, despite binding to the BIR domains of XIAP; however, FAF1 does attenuate XIAP-mediated NF-κB activation. Altered expression of both factors has been implicated in degenerative and cancerous processes; therefore, studying the balance between XIAP and FAF1 in these pathologies will aid in the development of novel therapies.
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http://dx.doi.org/10.1016/j.bbamcr.2017.04.006DOI Listing
July 2017

c-Abl Inhibitors Enable Insights into the Pathophysiology and Neuroprotection in Parkinson's Disease.

Front Aging Neurosci 2016 26;8:254. Epub 2016 Oct 26.

Institute of Biotechnology, University of Helsinki Helsinki, Finland.

Parkinson's disease (PD) is a progressive neurodegenerative disorder causing movement disabilities and several non-motor symptoms in afflicted patients. Recent studies in animal models of PD and analyses of brain specimen from PD patients revealed an increase in the level and activity of the non-receptor tyrosine kinase Abelson (c-Abl) in dopaminergic neurons with phosphorylation of protein substrates, such as α-synuclein and the E3 ubiquitin ligase, Parkin. Most significantly inhibition of c-Abl kinase activity by small molecular compounds used in the clinic to treat human leukemia have shown promising neuroprotective effects in cell and animal models of PD. This has raised hope that similar beneficial outcome may also be observed in the treatment of PD patients by using c-Abl inhibitors. Here we highlight the background for the current optimism, reviewing c-Abl and its relationship to pathophysiological pathways prevailing in PD, as well as discussing issues related to the pharmacology and safety of current c-Abl inhibitors. Clearly more rigorously controlled and well-designed trials are needed before the c-Abl inhibitors can be used in the neuroclinic to possibly benefit an increasing number of PD patients.
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http://dx.doi.org/10.3389/fnagi.2016.00254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5080529PMC
October 2016

[The pathogenesis of amyotrophic lateral sclerosis and frontal lobe dementia is unraveling: pathology of the nucleus and glutamate sensitivity].

Duodecim 2016 ;132(5):423-31

The mechanisms of neurodegenerative diseases have begun to become unraveled, thanks to the progress in stem cell research. The repeat expansion in the C90RF72 gene was identified in 2011 as the most common genetic cause of both ALS and frontal lobe dementia. Only over a couple of years the disease mechanisms of this mutation have been revealed and treatment trials have already been conducted in nerve cell cultures differentiated from patients' stem cells. We discuss the role of the repeat expansion in the C90RF72 gene in the epidemiology of the diseases and the resulting disturbances in nerve cell function.
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May 2016

p75 Neurotrophin Receptor Signaling Activates Sterol Regulatory Element-binding Protein-2 in Hepatocyte Cells via p38 Mitogen-activated Protein Kinase and Caspase-3.

J Biol Chem 2016 May 16;291(20):10747-58. Epub 2016 Mar 16.

From the Medicum, Department of Biochemistry and Developmental Biology, Medical Faculty, University of Helsinki, P. O. Box 63, Helsinki FIN-00014, Finland, the Minerva Foundation Institute for Medical Research, Biomedicum-2, Tukholmankatu 8, FIN-00290 Helsinki, Finland,

Nerve growth factor (NGF) influences the survival and differentiation of a specific population of neurons during development, but its role in non-neuronal cells has been less studied. We observed here that NGF and its pro-form, pro-NGF, are elevated in fatty livers from leptin-deficient mice compared with controls, concomitant with an increase in low density lipoprotein receptors (LDLRs). Stimulation of mouse primary hepatocytes with NGF or pro-NGF increased LDLR expression through the p75 neurotrophin receptor (p75NTR). Studies using Huh7 human hepatocyte cells showed that the neurotrophins activate the sterol regulatory element-binding protein-2 (SREBP2) that regulates genes involved in lipid metabolism. The mechanisms for this were related to stimulation of p38 mitogen-activated protein kinase (p38 MAPK) and activation of caspase-3 and SREBP2 cleavage following NGF and pro-NGF stimulations. Cell fractionation experiments showed that caspase-3 activity was increased particularly in the membrane fraction that harbors SREBP2 and caspase-2. Experiments showed further that caspase-2 interacts with pro-caspase-3 and that p38 MAPK reduced this interaction and caused caspase-3 activation. Because of the increased caspase-3 activity, the cells did not undergo cell death following p75NTR stimulation, possibly due to concomitant activation of nuclear factor-κB (NF-κB) pathway by the neurotrophins. These results identify a novel signaling pathway triggered by ligand-activated p75NTR that via p38 MAPK and caspase-3 mediate the activation of SREBP2. This pathway may regulate LDLRs and lipid uptake particularly after injury or during tissue inflammation accompanied by an increased production of growth factors, including NGF and pro-NGF.
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http://dx.doi.org/10.1074/jbc.M116.722272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4865921PMC
May 2016

Parkinson's disease: towards better preclinical models and personalized treatments.

Cell Mol Life Sci 2016 Apr 3;73(7):1383-5. Epub 2016 Feb 3.

Institute of Biotechnology, University of Helsinki, P.O.Box 56, Viikinkaari 9, 00014, Helsinki, Finland.

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http://dx.doi.org/10.1007/s00018-016-2141-1DOI Listing
April 2016

Peroxisome proliferator-activated receptor-γ coactivator-1α mediates neuroprotection against excitotoxic brain injury in transgenic mice: role of mitochondria and X-linked inhibitor of apoptosis protein.

Eur J Neurosci 2016 Mar 11;43(5):626-39. Epub 2016 Feb 11.

Medicum, Department of Biochemistry and Developmental Biology, Medical Faculty, University of Helsinki, POB 63, 00014, Haartmaninkatu 8, FIN-00290, Helsinki, Finland.

Peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) is a transcriptional coactivator involved in the regulation of mitochondrial biogenesis and cell defense. The functions of PGC-1α in physiology of brain mitochondria are, however, not fully understood. To address this we have studied wild-type and transgenic mice with a two-fold overexpression of PGC-1α in brain neurons. Data showed that the relative number and basal respiration of brain mitochondria were increased in PGC-1α transgenic mice compared with wild-type mitochondria. These changes occurred concomitantly with altered levels of proteins involved in oxidative phosphorylation (OXPHOS) as studied by proteomic analyses and immunoblottings. Cultured hippocampal neurons from PGC-1α transgenic mice were more resistant to cell degeneration induced by the glutamate receptor agonist kainic acid. In vivo kainic acid induced excitotoxic cell death in the hippocampus at 48 h in wild-type mice but significantly less so in PGC-1α transgenic mice. However, at later time points cell degeneration was also evident in the transgenic mouse hippocampus, indicating that PGC-1α overexpression can induce a delay in cell death. Immunoblotting showed that X-linked inhibitor of apoptosis protein (XIAP) was increased in PGC-1α transgenic hippocampus with no significant changes in Bcl-2 or Bcl-X. Collectively, these results show that PGC-1α overexpression contributes to enhanced neuronal viability by stimulating mitochondria number and respiration and increasing levels of OXPHOS proteins and the anti-apoptotic protein XIAP.
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http://dx.doi.org/10.1111/ejn.13157DOI Listing
March 2016

Peroxisome proliferator-activated receptor-γ (PPARγ) agonist is neuroprotective and stimulates PGC-1α expression and CREB phosphorylation in human dopaminergic neurons.

Neuropharmacology 2016 Mar 26;102:266-75. Epub 2015 Nov 26.

Medicum, Department of Biochemistry and Developmental Biology, Faculty of Medicine, PO Box 63, FIN-00014, University of Helsinki, Finland; Minerva Foundation Institute for Medical Research, Biomedicum Helsinki 2U, Tukholmankatu 8, FIN-00290, Helsinki, Finland. Electronic address:

Mitochondrial dysfunction has been linked to several neurodegenerative diseases such as Parkinson's disease (PD). Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a master gene for mitochondrial biogenesis and has been shown to be neuroprotective in models of PD. In this work we have studied the mechanisms by which peroxisome proliferator-activated receptor-γ (PPARγ) selective agonist N-(2-benzoylphenyl)-O-[2-(methyl-2-pyridinylamino)ethyl]-l-tyrosine hydrate (GW1929) acts on human dopaminergic neurons in culture. Data showed that GW1929 increased the viability of human dopaminergic neurons and protected them against oxidative stress induced by H2O2 and the mitochondrial toxin Rotenone. The enhanced resilience of the neurons was attributed to increased levels of mitochondrial antioxidants and of PGC-1α. GW1929 treatment further increased cell respiration, mitochondrial biogenesis and sirtuin-1 (SIRT1) expression in the human dopaminergic neurons. Phosphorylation of cAMP responsive element-binding protein (CREB) was also robustly increased in GW1929-treated cells. Together these results show that the PPARγ agonist GW1929 influences CREB signaling and PGC-1α activities in the human dopaminergic neurons contributing to an increased cell viability. This supports the view that drugs acting on the PPARγ-PGC-1α signaling in neurons may have beneficial effects in PD and possible also in other brain disorders.
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http://dx.doi.org/10.1016/j.neuropharm.2015.11.020DOI Listing
March 2016

Current disease modifying approaches to treat Parkinson's disease.

Cell Mol Life Sci 2016 Apr 30;73(7):1365-79. Epub 2015 Nov 30.

Institute of Biotechnology, University of Helsinki, P.O.Box 56, Viikinkaari 9, 00014, Helsinki, Finland.

Parkinson's disease (PD is a progressive neurological disorder characterized by the degeneration and death of midbrain dopamine and non-dopamine neurons in the brain leading to motor dysfunctions and other symptoms, which seriously influence the quality of life of PD patients. The drug L-dopa can alleviate the motor symptoms in PD, but so far there are no rational therapies targeting the underlying neurodegenerative processes. Despite intensive research, the molecular mechanisms causing neuronal loss are not fully understood which has hampered the development of new drugs and disease-modifying therapies. Neurotrophic factors are by virtue of their survival promoting activities attract candidates to counteract and possibly halt cell degeneration in PD. In particular, studies employing glial cell line-derived neurotrophic factor (GDNF) and its family member neurturin (NRTN), as well as the recently described cerebral dopamine neurotrophic factor (CDNF) and the mesencephalic astrocyte-derived neurotrophic factor (MANF) have shown positive results in protecting and repairing dopaminergic neurons in various models of PD. Other substances with trophic actions in dopaminergic neurons include neuropeptides and small compounds that target different pathways impaired in PD, such as increased cell stress, protein handling defects, dysfunctional mitochondria and neuroinflammation. In this review, we will highlight the recent developments in this field with a focus on trophic factors and substances having the potential to beneficially influence the viability and functions of dopaminergic neurons as shown in preclinical or in animal models of PD.
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http://dx.doi.org/10.1007/s00018-015-2101-1DOI Listing
April 2016

Nerve growth factor (NGF) and pro-NGF increase low-density lipoprotein (LDL) receptors in neuronal cells partly by different mechanisms: role of LDL in neurite outgrowth.

J Neurochem 2016 Jan 19;136(2):306-15. Epub 2015 Nov 19.

Department of Biochemistry and Developmental Biology, Medical Faculty, Medicum, University of Helsinki, Helsinki, Finland.

Low-density lipoprotein receptors (LDLRs) mediate the uptake of lipoprotein particles into cells, as studied mainly in peripheral tissues. Here, we show that nerve growth factor (NGF) increases LDLR levels in PC6.3 cells and in cultured septal neurons from embryonic rat brain. Study of the mechanisms showed that NGF enhanced transcription of the LDLR gene, acting mainly via Tropomyosin receptor kinase A receptors. Simvastatin, a cholesterol-lowering drug, also increased the LDLR expression in PC6.3 cells. In addition, pro-NGF and pro-brain-derived neurotrophic factor, acting via the p75 neurotrophin receptor (p75NTR) also increased LDLRs. We further observed that Myosin Regulatory Light Chain-Interacting Protein/Inducible Degrader of the LDLR (Mylip/Idol) was down-regulated by pro-NGF, whereas the other LDLR regulator, proprotein convertase subtilisin kexin 9 (PCSK9) was not significantly changed. On the functional side, NGF and pro-NGF increased lipoprotein uptake by neuronal cells as shown using diacetyl-labeled LDL. The addition of serum-derived lipoprotein particles in conjunction with NGF or simvastatin enhanced neurite outgrowth. Collectively, these results show that NGF and simvastatin are able to stimulate lipoprotein uptake by neurons with a positive effect on neurite outgrowth. Increases in LDLRs and lipoprotein particles in neurons could play a functional role during brain development, in neuroregeneration and after brain injuries. Nerve growth factor (NGF) and pro-NGF induce the expression of low-density lipoprotein receptors (LDLRs) in neuronal cells leading to increased LDLR levels. Pro-NGF also down-regulated myosin regulatory light chain-interacting protein/inducible degrader of the LDLR (Mylip/Idol) that is involved in the degradation of LDLRs. NGF acts mainly via Tropomyosin receptor kinase A (TrkA) receptors, whereas pro-NGF stimulates p75 neurotrophin receptor (p75NTR). Elevated LDLRs upon NGF and pro-NGF treatments enhanced lipoprotein uptake by neurons. Addition of LDL particles further led to the stimulation of neurite outgrowth in PC6.3 cells after NGF or simvastatin treatments, suggesting a stimulatory role of lipoproteins on neuronal differentiation. In contrast, pro-NGF had no effect on neurite outgrowth either in the absence or presence of LDL particles. The precise mechanisms by which increased lipoproteins uptake can affect neurite outgrowth warrant further studies.
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http://dx.doi.org/10.1111/jnc.13397DOI Listing
January 2016

Stem cell therapy: how to do it right.

Front Cell Dev Biol 2014 6;2:66. Epub 2014 Nov 6.

Institute of Biomedicine/Biochemistry and Developmental Biology, University of Helsinki Helsinki, Finland ; Minerva Medical Research Institute Helsinki, Finland.

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http://dx.doi.org/10.3389/fcell.2014.00066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4222350PMC
November 2014

Ubiquitin-specific protease-14 reduces cellular aggregates and protects against mutant huntingtin-induced cell degeneration: involvement of the proteasome and ER stress-activated kinase IRE1α.

Hum Mol Genet 2014 Nov 20;23(22):5928-39. Epub 2014 Jun 20.

Institute of Biomedicine/Biochemistry and Developmental Biology, University of Helsinki, Helsinki FIN-00290, Finland, Minerva Foundation Institute for Medical Research, Helsinki, Finland, Division of Child Psychiatry, Helsinki University Central Hospital, Helsinki, Finland.

Huntington's disease (HD) is an autosomal inherited neurological disease caused by a CAG-repeat expansion in the first exon of huntingtin gene encoding for the huntingtin protein (Htt). In HD, there is an accumulation of intracellular aggregates of mutant Htt that negatively influence cellular functions. The aggregates contain ubiquitin, and part of the HD pathophysiology could result from an imbalance in cellular ubiquitin levels. Deubiquitinating enzymes are important for replenishing the ubiquitin pool, but less is known about their roles in brain diseases. We show here that overexpression of the ubiquitin-specific protease-14 (Usp14) reduces cellular aggregates in mutant Htt-expressing cells mainly via the ubiquitin proteasome system. We also observed that the serine-threonine kinase IRE1 involved in endoplasmic reticulum (ER) stress responses is activated in mutant Htt-expressing cells in culture as well as in the striatum of mutant Htt transgenic (BACHD) mice. Usp14 interacted with IRE1 in control cells but less in mutant Htt-expressing cells. Overexpression of Usp14 in turn was able to inhibit phosphorylation of IRE1α in mutant Htt-overexpressing cells and to protect against cell degeneration and caspase-3 activation. These results show that ER stress-mediated IRE1 activation is part of mutant Htt toxicity and that this is counteracted by Usp14 expression. Usp14 effectively reduced cellular aggregates and counteracted cell degeneration indicating an important role of this protein in mutant Htt-induced cell toxicity.
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http://dx.doi.org/10.1093/hmg/ddu317DOI Listing
November 2014

Diabetes drugs and neurological disorders: new views and therapeutic possibilities.

Lancet Diabetes Endocrinol 2014 Mar 22;2(3):256-62. Epub 2013 Nov 22.

Institute of Biomedicine/Biochemistry and Developmental Biology, University of Helsinki, Biomedicum, Finland; Minerva Medical Research Institute, Helsinki, Finland. Electronic address:

Type 2 diabetes is a metabolic disease characterised by insulin resistance with hyperglycaemia and dyslipidaemia. It is associated with increased risk of stroke and vascular dementia, and might contribute to the development of Alzheimer's disease. Recent studies have shown that several antidiabetic drugs can promote neuronal survival and lead to a significant clinical improvement of memory and cognition in different clinical settings. We discuss these emerging data, with a focus on metformin, thiazolidinediones, and the more recently developed compounds targeting the glucagon-like peptide-1 receptor. Data show that these antidiabetic drugs affect brain metabolism, neuroinflammation, and regeneration. Evidence thus far strongly indicates that these antidiabetic drugs could be developed as disease-modifying therapies for human brain diseases in patients with and without diabetes.
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http://dx.doi.org/10.1016/S2213-8587(13)70125-6DOI Listing
March 2014

Fibroblast growth factor-21 enhances mitochondrial functions and increases the activity of PGC-1α in human dopaminergic neurons via Sirtuin-1.

Springerplus 2014 2;3. Epub 2014 Jan 2.

Institute of Biomedicine/Biochemistry and Developmental Biology, University of Helsinki, Haartmaninkatu 8, FIN-00290 Helsinki, Finland ; Minerva Foundation Institute for Medical Research, Biomedicum-2, FIN-00290 Helsinki, Finland.

Mitochondrial dysfunctions accompany several neurodegenerative disorders and contribute to disease pathogenesis among others in Parkinson's disease (PD). Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is a major regulator of mitochondrial functions and biogenesis, and was suggested as a therapeutic target in PD. PGC-1α is regulated by both transcriptional and posttranslational events involving also the action of growth factors. Fibroblast growth factor-21 (FGF21) is a regulator of glucose and fatty acid metabolism in the body but little is known about its action in the brain. We show here that FGF21 increased the levels and activity of PGC-1α and elevated mitochondrial antioxidants in human dopaminergic cells in culture. The activation of PGC-1α by FGF21 occurred via the NAD(+)-dependent deacetylase Sirtuin-1 (SIRT1) subsequent to an increase in the enzyme, nicotinamide phosphoribosyltransferase (Nampt). FGF21 also enhanced mitochondrial respiratory capacity in human dopaminergic neurons as shown in real-time analyses of living cells. FGF21 is present in the brain including midbrain and is expressed by glial cells in culture. These results show that FGF21 activates PGC-1α and increases mitochondrial efficacy in human dopaminergic neurons suggesting that FGF21 could potentially play a role in dopaminergic neuron viability and in PD.
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http://dx.doi.org/10.1186/2193-1801-3-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409609PMC
May 2015

Reciprocal regulation of very low density lipoprotein receptors (VLDLRs) in neurons by brain-derived neurotrophic factor (BDNF) and Reelin: involvement of the E3 ligase Mylip/Idol.

J Biol Chem 2013 Oct 29;288(41):29613-20. Epub 2013 Aug 29.

From the Institute of Biomedicine/Biochemistry and Developmental Biology, University of Helsinki and.

BDNF positively influences various aspects of neuronal migration, maturation, and survival in the developing brain. Reelin in turn mediates inhibitory signals to migrating neuroblasts, which is crucial for brain development. The interplay between BDNF and Reelin signaling in neurodevelopment is not fully understood. We show here that BDNF increased the levels of the Reelin receptor (VLDL receptor (VLDLR)) in hippocampal neurons by increasing gene expression. In contrast, Reelin decreased VLDLRs, which was accompanied by an increase in the levels of the E3 ligase Mylip/Idol in neurons. Down-regulation of Mylip/Idol using shRNAs abrogated the decrease in VLDLRs induced by Reelin. These results show that VLDLRs are tightly regulated in hippocampal neurons by both transcriptional and post-transcriptional mechanisms. The regulation of VLDLR by BDNF and Reelin may affect the migration of neurons and contribute to neurodevelopmental disorders in the nervous system.
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http://dx.doi.org/10.1074/jbc.M113.500967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3795259PMC
October 2013

Hepatocyte growth factor activator inhibitor-1 is induced by bone morphogenetic proteins and regulates proliferation and cell fate of neural progenitor cells.

PLoS One 2013 7;8(2):e56117. Epub 2013 Feb 7.

Institute of Biomedicine/Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland.

Background: Neural progenitor cells (NPCs) in the developing neuroepithelium are regulated by intrinsic and extrinsic factors. There is evidence that NPCs form a self-supporting niche for cell maintenance and proliferation. However, molecular interactions and cell-cell contacts and the microenvironment within the neuroepithelium are largely unknown. We hypothesized that cellular proteases especially those associated with the cell surface of NPCs play a role in regulation of progenitor cells in the brain.

Methodology/principal Findings: In this work, we show that NPCs, isolated from striatal anlage of developing rat brain, express hepatocyte growth factor activator inhibitor-1 and -2 (HAI-1 and HAI-2) that are cell surface-linked serine protease inhibitors. In addition, radial glia cells derived from mouse embryonic stem cells also express HAI-1 and HAI-2. To study the functional significance of HAI-1 and HAI-2 in progenitor cells, we modulated their levels using expression plasmids or silencing RNA (siRNA) transfected into the NPCs. Data showed that overexpression of HAI-1 or HAI-2 decreased cell proliferation of cultured NPCs, whilst their siRNAs had opposite effects. HAI-1 also influenced NPC differentiation by increasing the number of glial fibrillary acidic protein (GFAP) expressing cells in the culture. Expression of HAI-1 in vivo decreased cell proliferation in developing neuroepithelium in E15 old animals and promoted astrocyte cell differentiation in neonatal animals. Studying the regulation of HAI-1, we observed that Bone morphogenetic protein-2 (BMP-2) and BMP-4 increased HAI-1 levels in the NPCs. Experiments using HAI-1-siRNA showed that these BMPs act on the NPCs partly in a HAI-1-dependent manner.

Conclusions: This study shows that the cell-surface serine protease inhibitors, HAI-1 and HAI-2 influence proliferation and cell fate of NPCs and their expression levels are linked to BMP signaling. Modulation of the levels and actions of HAI-1 in NPCs may be of a potential value in stem cell therapies in various brain diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0056117PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567048PMC
July 2013
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