Kan datamodeller hjelpe oss å forstå kompliserte sykdommer?

SciLifeLab1

Foto: Rune Kleppe

Mange psykiske lidelser har en høy arvelig komponent. Man tror likevel at det underliggende genetiske bildet er svært sammensatt, og at mange ulike gener bidrar til økt sårbarhet for å utvikle slike lidelser. Endringer i gener kan gi opphav til proteiner (molekylære maskiner) med nye egenskaper, eller endre nivået av proteinene i cellene. Siden mange ulike proteiner deltar i hver prosess som foregår i cellene, er det likevel ikke alltid enkelt å forutsi om slike endringer vil ha noen innvirkning på prosessene som helhet. For mange cellulære prosesser har man kunnskap om mekanistiske detaljer på hvordan proteinene fungerer. Denne kunnskapen kan brukes til å generere datamodeller av de aktuelle prosessene, noe vi kaller systembiologiske modeller. Slike modeller beskriver matematisk hvordan ulike molekyler samvirker med hverandre i cellen og dermed også hvordan molekylenes egenskaper, eller endring i disse, påvirker prosessen som helhet.

Flere cellulære prosesser anses å være avgjørende for utvikling av psykiatriske lidelser. Dette inkluderer prosesser som fører til dannelse av stabile koblinger mellom ulike nerveceller, prosesser som styrer nervecellers evne til å respondere på stimuli og som styrer deres plastisitet. Plastisitet er molekylære endringer som forsterker eller svekker koblinger mellom nerveceller (synapser) ved at responsmønster og følsomhet blir forandret ut fra tidligere aktivitet i synapsene.

Vi ønsker derfor å undersøke om sårbarhetsgener som deltar i slike nøkkelprosesser, kan forstås bedre i lys av systemmodeller. Vi ønsker å koble sammen slike modeller med genetiske analyser av pasientmateriale for å bedre forstå hvordan endringer i flere gener kan sammen bidra til å utvikle psykiatriske lidelser. Vårt hovedfokus er på ADHD og prosjektet er også støttet av Nasjonalt kompetansesenter for nevroutviklingsforstyrrelser og hypersomnier (NevSom).

I prosjektet samarbeider vi bl.a. med forskningsgruppen til Prof. Jeanette Hellgren Kotaleski ved Karolinska institutet/KTH i Stockholm og nå senhøstes var forsker Rune Kleppe på besøk for å arbeide på prosjektet. Kotaleskis forskningsgruppe er eksperter på datasimuleringer av nervekretser og signalprosesser i nerveceller. Gruppen er lokalisert i Science for Life Laboratory (SciLifeLab) bygningen, rett ved siden av Karolinska Institutet. I SciLifeLab holder også prosjekter som det nasjonale genomics infrastrukturen og det humane proteomikk atlas til.

Av Rune Kleppe

KGJN til stede på medisinstudentenes forskningskonferanse, Frampeik

Kvadsheim holdt en presentasjon om hjerteratevariabilitet hos barn med ADHD og angst
Kvadsheim holdt en presentasjon om hjerteratevariabilitet hos barn med ADHD og angst

30. oktober til 1. november ble medisinstudentenes årlige forskningskonferanse, Frampeik, avholdt. De fire byene Oslo, Bergen, Trondheim og Tromsø veksler på å avholde arrangementet, og i år var det idylliske Tromsø sin tur.

Elisabet Kvadsheim, forskerlinjestudent ved UiB og medlem av KGJN, deltok på konferansen. Forskerlinjen gir medisinstudenter mulighet til å arbeide i en forskningsgruppe parallelt med studiene, og i år har Kvadsheim fulltidspermisjon for å fokusere på forskningen. Hun undersøker hvordan det autonome (ikke-viljestyrte) nervesystemet fungerer hos barn og ungdom med ADHD og angst, ved bruk av et mål kalt hjerteratevariabilitet.

Frampeik gir medisinstudenter som forsker muligheten til å presentere sine prosjekter. Det var et stort spenn i tematikken – alt fra biomarkører og medikamentutprøving til Kvadsheims forskning på ADHD. Kvadsheim fikk flere spørsmål fra salen etter presentasjonen, som kan tyde på at deltakerne syntes dette er et viktig og interessant forskningsområde.

Daniel Jensen

Report from Tetyana and her Collaboration at BROAD

bussholdeplass broad
DataStream at DNAtrium, Broad Institute (Photo: Len Rubenstein)

During this year, I’ve spent two fortnights at BROAD Institute of MIT and Harvard (https://www.broadinstitute.org) to work on the genetics of ADHD. The first fortnight was in February of 2015, when I was working on the rare variant associations (exome chip content) in adult ADHD. This project is a collaborative effort within IMpACT consortium (http://www.webdesign-rijen.nl/impact/ ) led by our group at Jebsen center. The work has since been finished and we are in the process of publishing the manuscript.

 

The second fortnight was spent at BROAD in November 2015. This time I was working on the identification of copy number variations (CNVs) related to ADHD. Similarly to the previous project, this is a collaborative effort within Psychiatric Genomics Consortium (PGC, https://www.med.unc.edu/pgc ) that our group is leading. This is the largest CNV study in ADHD, involving over 5.000 cases and 10.000 controls. Future plans of this project involve further work at BROAD in 2016.

Tetyana Zayats

Reduced error signalling in medication-naive children with ADHD

Kerstin J. Plessen, MD, PhD; Elena A. Allen, PhD; Heike Eichele, MD; Heidi van Wageningen, Phd; Marie Farstad Høvik, MD; Lin Sørensen, PhD; Marius Kalsås Worren, MD; Kenneth Hugdahl, PhD; Tom Eichele, MD,PhD

Background: 

We examined the blood-oxygen level–dependent (BOLD) activation in brain regions that signal errors and their association with intraindividual behavioural variability and adaptation to errors in children with attention-deficit/hyperactivity disorder (ADHD).

Methods:

©PHOTOPQR/LE REPUBLICAIN LORRAIN/BROCARD Pascal jeux en cour de recreation a jussy (moselle)
©PHOTOPQR/LE REPUBLICAIN LORRAIN/BROCARD Pascal
jeux en cour de recreation a jussy (Moselle)

We acquired functional MRI data during a Flanker task in medication-naive children with ADHD and healthy controls aged 8–12 years and analyzed the data using independent component analysis. For components corresponding to performance monitoring networks, we compared activations across groups and conditions and correlated them with reaction times (RT). Additionally, we analyzed post-error adaptations in behaviour and motor component activations.

Results:

We included 25 children with ADHD and 29 controls in our analysis. Children with ADHD displayed reduced activation to errors in cingulo-opercular regions and higher RT variability, but no differences of interference control. Larger BOLD amplitude to error trials significantly predicted reduced RT variability across all participants. Neither group showed evidence of post-error response slowing; however, post-error adaptation in motor networks was significantly reduced in children with ADHD. This adaptation was inversely related to activation of the right-lateralized ventral attention network (VAN) on error trials and to taskdriven connectivity between the cingulo-opercular system and the VAN.

Limitations: 

Our study was limited by the modest sample size and imperfect matching across groups.

Conclusion:

Our findings show a deficit in cingulo-opercular activation in children with ADHD that could relate to reduced signalling for errors. Moreover, the reduced orienting of the VAN signal may mediate deficient post-error motor adaptions. Pinpointing general performance monitoring problems to specific brain regions and operations in error processing may help to guide the targets of future treatments for ADHD.

Read the article here:

Reduced error signalling in medication-naive children with ADHD: Associations with behavioural variability and post-error adaptations.

Report from the 45th Neuroscience (SfN) meeting in Chicago

The annual meeting of the Society for Neuroscience (SfN) is the largest neuroscience meeting where thousands of neuroscientists from around the world gather to discuss cutting edge research. The meeting includes lectures, symposia, workshops and events for scientist at all career stages. This is a place where neuroscientist presents their science, learn from experts, initiate collaborations with peers, explore new tools and technologies and advance their careers. The themes cover everything from detailed studies on fine-tuned regulation of molecules dictating the function of neuronal cells to genetic and epidemiological studies of diseases affecting the brain.
The hot topic for this year’s meeting was novel tool developments and applications for temporal and spatial regulation of gene expression, so called optogenetics. Optogenetics involves the use of light to control the activity of cells in living tissue. This approach of genetic manipulation gives enormous potential for basic research, because nerve excitation and silencing can be performed simply by light with high precisions in a reversible manner.
The Norwegian neuroscience community was well represented by members from all over the country and May-Britt Moser (2014 Nobel Prize winner in Medicine and Physiology) from the Kavli Institute for Systems Neuroscience and the Norwegian University of Science and Technology (NTNU) held a presidential lecture about grid cells and cortical maps of space. The neuroscience group from the KB Jebsen center was also well represented by Professor Clive Bramham, senior researcher Oleksii Nikolaienko, postdoc Sudarshan Patil and lab manager Tambudzai Kanhema Jakobsen.

SfN2015_1

Group dinner in Chicago after a long day at the SfN. Starting from the left we have Oleksii Nikolaienko, Tambudzai Kanhema Jakobsen, Sudarshan Patil, Clive Bramham and 2 colleagues of Clive.

Sudarshan is giving his view of the meeting below:

“The SfN 2015 annual meeting is a great opportunity for neuroscientists from the whole world to come together. This was the first time I attended the SfN and I was lucky enough to receive traveling money from the Meltzer foundation. In Chicago the meeting was held in a big venue holding more than 28000 attendees under one roof and a lot of great science was shared. Importantly, I was mesmerized with attendees visiting my poster presented on “Regulation of Arc protein by SUMOylation during LTP in the adult dentate gyrus in vivo”. It was a great opportunity for me to discuss my science with other researchers including specialists in the field. I also received updated views from experts about present emerging science. Moreover it helped to tie up new collaborations with peers, explore new tools and technologies, and advance careers.”

SfN2015_2

Sudarshan Patil is presenting his poster.

Sudarshan Patil and Tambudzai Kanhema Jakobsen have contributed to the text and Karin Wibrand did the editing.

 

Parent of origin effects – a path forward for ADHD genetics?

Parent of origin effect

From Zayats et al. 2015 Behav. Brain Funct. 11, 33

A gene variant may contribute differently to a change in phenotype, or to the development of a disease, depending on if it is inherited from the mother or the father. Such a difference between maternal and paternal inheritance is referred to as parent-of-origin effect and this effect may be important for understanding aspects of ADHD and related behavioral phenotypes.

Genome-wide association (GWA) studies have shown that many different genetic variants cumulatively contribute to the risk of psychiatric disorders. It has also been demonstrated that various parent-of-origin effects (POE) may differentially influence the risk of these disorders. Together, these observations have provided important new possibilities to uncover the genetic underpinnings of such complex phenotypes. As POE so far have received little attention in neuropsychiatric disorders, there is still much progress to be made. In a recent review article on the subject, we focus on the new and emerging role of POE in attention-deficit hyperactivity disorder (ADHD). We review the current evidence that POE play an imperative role in vulnerability to ADHD and related disorders. We also discuss how POE can be assessed using statistical genetics tools, expanding the resources of modern psychiatric genetics. We propose that better comprehension and inspection of POE may offer new insight into the molecular basis of ADHD and related phenotypes, as well as the potential for preventive and therapeutic interventions.

By Tetyana Zayats (researcher in the KGJN), edited by Rune Kleppe

Mammalian CSAD and GADL1 have distinct biochemical properties and patterns of brain expression

Every year, millions of people consume tons of dietary supplements. In particular, the claimed ergogenic properties of β-alanine and taurine (2-amino-ethanesulfonic acid) have made these amino acids extremely popular particularly among young people and they are widely used by athletes world-wide. Taurine is abundant in many mammalian tissues and has been implicated in a range of different physiological functions. It has a well-documented regulatory role in maintenance of osmotic pressure and preservation of structural integrity of biological membranes. In the nervous system, taurine may modulate protein phosphorylation, serve as a trophic factor, or act as a neurotransmitter / neuromodulator. In several species, taurine deficiency has been linked with specific disease states and also in humans altered levels of taurine has been reported in different conditions, including ADHD and autism. The related amino acid β-alanine, generated from aspartate, and its dipeptide derivative carnosine have also been proposed to have many health benefits.

In this article we have tried to expand the knowledge base for these substances by provide new fundamental insights into the biosynthesis of these amino acids and their derivatives in mice and man, in particular regarding the roles of the biosynthetic enzymes CSAD and GADL1 at the cellular and organ level and determine their expression levels during pre/postnatal development.

In the present study, we compared the catalytic properties, inhibitor sensitivity and expression profiles of GADL1 and CSAD in brain tissue. In mouse and human brain we observed distinct patterns of expression of the PLP-dependent decarboxylases CSAD, GADL1 and glutamic acid decarboxylase 67 (GAD67). CSAD levels were highest during prenatal and early postnatal development; GADL1 peaked early in prenatal development, while GAD67 increased rapidly after birth. Both CSAD and GADL1 are being expressed in neurons, whereas only CSAD mRNA was detected in astrocytes. Cysteine sulfinic acid was the preferred substrate for both mouse CSAD and GADL1, although both enzymes also decarboxylated cysteic acid and aspartate.

In silico screening and molecular docking using the crystal structure of CSAD and in vitro assays led to the discovery of eight new enzyme inhibitors with partial selectivity for either CSAD or GADL1. Lithium had minimal effect on their enzyme activities. In conclusion, taurine biosynthesis in vertebrates involves two structurally related PLP-dependent decarboxylases (CSAD and GADL1) that have partially overlapping catalytic properties but different tissue distribution, indicating divergent physiological roles. Development of selective enzyme inhibitors targeting these enzymes is important to further dissect their (patho)physiological roles.

 

S01970186

Mammalian CSAD and GADL1 have distinct biochemical properties and patterns of brain expression

 

 

KGJN tilstades på det første nordiske neurosciencemøtet

NordicNeuroscience2015

Nordic Neuroscience vart arrangert for fyrste gong 10 -12 juni i år. Konferansen fann stad på NTNU på Gløshaugen i Trondheim og programmet var fylt opp med interessante foredrag, blant anna frå våre Nobelprisvinnarar.

Det var ein god gjeng frå KGJN som tok turen, spesielt var Bramham og Haavik sine forskingsgrupper godt representerte. Me fekk ei omvising på universitetsområdet før me vart registrerte for konferansen. Dei tre dagane bydde på ei lang rekkje spennande foredrag.

Blant høgdepunkta var, forutan ekteparet Moser sin presentasjon «The Brain’s Map of Space», David Andersons utgreiing om «Neural Circuit Modules for Social Behaviors» og Silvia Arber sitt foredrag om «Disentangling Descending Circuits for Motor Control». I tillegg til hovudforelesingane var det mange interessante symposia, mellom anna «Molecular Mechanisms of Drug Abuse», «Neurotransmitter Transporters in Pathophysiology» og «Cortex: Organization and Dynamics in Normal Brains and in Disease». Dei tilreisande frå UiB bidrog med fleire plakatar, og presenterte desse på torsdagen, innimellom symposia. Det oppstod mange spennande diskusjonar og meiningsutvekslingar.

Kvelden onsdag og torsdag hadde arrangementskomiteen ordna med middag med noko godt i glaset til deltakarane på konferansen. Òg her vart det duka for gode diskusjonar og meir uformelle samtaler om alt frå det haustlege vêret til kompliserte nevrovitskaplege tema.

Me vil retta ein stor takk til arrangørane som gjorde eit særs godt arbeid med å stella til Nordic Neuroscience 2015 i Trondheim.

Tekst: Tore Ivar Aarsland

First Norwegian GWAs on ADHD

dna

Photo: pixabay

Attention deficit hyperactivity disorder (ADHD) is a highly heritable neuropsychiatric condition, but due to its complexity it has been challenging to identify genes underlying this disorder. Our genetics group at K.G.Jebsen center performed the first genome-wide association analyses of ADHD in an ethnically homogeneous Norwegian population.

Taken together with previous findings, our results point to a spectrum of biological mechanisms underlying the symptoms of ADHD, such as gene expression and cell adhesion, pointing towards neurogenesis and inflammation. This study confirms existing targets and provides new ones for further genetic exploration as well as treatment and prevention of this complex disorder.

Text by Tetyana Zayats (researcher, KGJN)

Link to article

Structural organization of the memory protein – Arc

AFMfigureArc

Figure: Human Arc protein, visualized via atomic force microscopy (AFM) by Anne Baumann.

In May 2011, a few months into my PhD, I took a Molecular and Computational Biology (MCB) Research School course called Recombinant proteins: Expression, Purification & Interaction Studies. Being the new, ambitious PhD candidate that I was, I started to discuss my project with fellow student, Helene Bustad Johannessen. It just so happened that her protein of interest was a proposed interaction partner with my protein. So, we made plans to test it out in the coming months. Though that specific project didn’t pan out, it was the start of a fruitful collaboration between my group (Prof. Clive Bramham) and Helene’s group (Prof. Aurora Martinez), which eventually led to last week’s publication in Biochemical Journal.

My PhD was on a protein called Arc, which is critical for long-term memory formation. Despite significant interest in Arc, nothing was known about its structure. Helene and I began by investigating Arc secondary structure with circular dichroism (CD). Anne Baumann and I learned more about Arc stability with dynamic light scattering (DLS), while Marte Innselset Flydal studied Arc stability with differential scanning calorimetry (DSC). Anne went on to do some important surface plasmon resonance (SPR) and CD experiments to show that recombinant Arc binds to a known binding partner, PS1. We also had excellent collaborators in France and Spain that added crucial parts to the paper.

Our paper is titled, Arc is a flexible modular protein capable of reversible self-oligomerization, and is the first biochemical and biophysical analysis of Arc structure and stability. We are excited about the follow-up projects on Arc structure with continued collaborations within the Jebsen Center!

Check out the paper (soon to be open access)

By Craig Myrum