2nd NO-Age Symposium: Genomic instability in human brain

The NO-Age Norwegian Centre on Healthy Ageing arranges its 2nd symposium on "Genomic instability in human brain".

NO-Age logo


Read a summary from the event 


Morning Session: Genomic instability in disease and ageing

Moderator: Hilde Nilsen

08:00-08:10: Opening speech Anne Rita Øksengård (The Norwegian Health Association)

08:10-08:20: Welcomw: Evandro Fang, Hilde Nilsen, and Linda Bergersen

View large poster

08:20-09:00 Vilhelm A. Bohr (NIA/USA, Copenhagen)

09:00-09:30: Peter McHugh (Oxford)

09:30-10:00: Tinna Stevnsner (Aarhus)

10:00-10:20: Break and networking

10:20-10:50: Magnar Bjoras (UiO and NTNU)

10:50-11:20: Hilde L. Nilsen (Ahus and UiO)

11:20-11:50: Arne Klungland (UiO)

11:50-12:10: Minoru Takata (Kyoto, Japan)

12:10-12:25: Jian XIAO and Jinsan ZHANG (WZMU, China)


Session theme: Advances in healthy brain ageing

Moderator: Evandro Fang

13:30-14:00:   Tormod Fladby (Ahus, UiO)

14:00-14:30:   Willam McEwan (Cambridge)

14:30-15:00:   Linda Bergersen (UiO and Copenhagen)

15:00-15:30:   Break and networking

15:30-16:00:   Evandro F. Fang (Ahus, UiO)

16:00-16:30:   Hansang Cho (University of North Carolina at Charlotte, USA)

16:30-17:00:   Leiv Otto Watne (UiO)

17:00-17:30:   Jens Pahnke (UiO)

More about NO-Age Norwegian Centre on Healthy Ageing


Please contact Dr. Evandro F. Fang (e.f.fang@medisin.uio.no) for any further queries

Speakers and abstracts

Vilhelm Bohr: DNA damage leads to mitochondrial dysfunction and neurodegeneration


We find that some DNA repair defective diseases with severe neurodegeneration have mitochondrial dysfunctiuon.  Our studies involve cell lines, the worm (c.elegans), and mouse models and include the premature aging syndromes Xeroderma pigmentosum group A, Cockaynes syndrome, Ataxia telangiectasia and Werner syndrome.  We find a pattern of hyperparylation, deficiency in the NAD+and Sirtuin signaling and mitochondrial stress.  We are pursuing mechanistic studies of this signaling and interventions at different steps to improve mitochondrial health and the neurodegeneration.  I will discuss intervention studies in these diseases models including a new Alzheimer mouse model using NAD supplementation.  NAD supplementation stimulates mitochondrial functions including mitophagy and stimulates DNA repair pathways.  Based on human postmortem material and IPSC cells we identify mitophagy defects as a prominent feature in Alzheimers disease (AD). Using c.elegans AD models we screened for mtophagy stimulators and identified compounds that subsequentially also show major improvement of AD features in mouse models.   


Dr. Bohr received his M.D. in 1978, Ph.D. in 1987, and D.Sc. in 1987 from the University of Copenhagen, Denmark. After training in neurology and infectious diseases at the University Hospital in Copenhagen, Dr. Bohr did a postdoctoral fellowship with Dr. Hans Klenow at the University of Copenhagen, Denmark. He then worked with Dr. Philip Hanawalt at Stanford University as a research scholar from 1982-1986. In 1986 he was appointed to the National Cancer Institute (NCI) as an investigator, becoming a tenured Senior Investigator in 1988. Dr. Bohr developed a research section in DNA repair at the NCI. In 1992 he moved to the NIA to become Chief of the Laboratory of Molecular Genetics. His main contributions have been in the area of DNA repair. He has worked on many aspects of DNA damage and its processing in mammalian cells. He developed a widely used method for the analysis of DNA repair in individual genes and found that active genes are preferentially repaired. This observation was a major advance in the clarification of the tight interaction between DNA repair and transcription, a process termed transcription-coupled repair. In recent years numerous papers from his laboratory have focused on mechanisms of DNA damage processing, particularly on nucleotide excision repair and transcription coupling. A main interest now is to elucidate how these processes change in relation to aging.

Tinna Stevnsner: Mitochondrial metabolism and DNA repair in maintenance of cognitive capacity at very old age


A growing proportion of the population is surviving to a very high age and cognitive changes as a normal process of aging is well documented. However, there are substantial individual differences in the rate and magnitude of age-associated cognitive decline. DNA repair capacity, optimal mitochondrial function and a sufficient level of NAD+/NADH are some of the factors, which seem to be essential for optimal brain function. In order to get insight into the molecular mechanisms involved in maintenance of cognitive capacity at very old age we are investigating potential associations between cognitive capacity in a cohort of Danish centenarians and the above-mentioned biomarkers in the blood. We find a positive correlation between NAD+/NADH levels in the centenarians’ plasma and their cognitive capacity. Our data reveal a negative correlation between cognitive capacity and the level of carbonylated proteins and APE1/Ref1 protein in plasma, respectively. When studying peripheral blood lymphocytes isolated from the blood samples of the centenarians we find a positive correlation between cognitive capacity and APE1 endonuclease amount and activity. Finally, mitochondrial respiratory measures were found to be significantly increased in males with low cognitive capacity. The observed associations contribute to an expanded insight into the potential role of a range of molecular factors involved in maintenance of cognitive capacity at old age and also point to metabolic pathways of particular importance.


Dr. Tinna Stevnsner is an associate professor and principal investigator in a research laboratory at Department of Molecular Biology and Genetics. Her research focuses on the role of nuclear and mitochondrial genome maintenance in aging. Recently, much of her research has been directed towards the elucidation of molecular pathways involved in maintenance of cognitive capacity at old age.

Tinna did her PhD work in the laboratory of Vilhelm A. Bohr at National Cancer Institute, NIH, USA, where she investigated aspects of gene specific repair in mammalian cells. Afterwards, she worked for four years as a post doc at Dep. of Environmental and Occupational Health at Aarhus University, Denmark, where she studied DNA repair capacities in cultured lymphoblastoid cells and PBMCs from patients suffering from premature aging syndromes and bladder cancer patients, respctively. Next, she moved on to her current place of work. In 2014 she visited the laboratory of prof. Carl Cotman at University of California, Irvine, USA, for six months. There, she investigated the age-associated expression of base excision repair (BER) proteins in different regions of the human brain and studied the potential role of Brain-derived neurotrophic factor (BDNF) in the regulation of BER in neurons.

Arne Klungland: Epitranscriptomic regulation neurodevelopment


 A broad repertoire of modifications is known to underlie adaptable function of proteins, DNA and RNA. Methylations of DNA and histone residues regulate transcription and the discoveries of demethylases that remove methylation in DNA and histones has led to a tremendous progress in the understanding of dynamic methyl marks in gene regulation (Feinberg, Nature 2007, 447:433-40, Shi et al., Cell 2004, 119:941-53). Post-transcriptional RNA modifications were identified several decades ago, but the reversible nature of RNA modifications has only recently been discovered (Jia et al., Nat Chem Biol 2011, 7:885-7; Zheng et al., Mol Cell 2013, 49:18-29). Our studies will focus on the role of readers and erasers of these dynamic methyl marks.

We and others have recently shown that a particular mark, N6-methyladenine (m6A) is highly prevalent and dynamically regulated in the brain. Furthermore, writers,  readers and erasers of m6A  is required for healthy neuronal development (Yoon et al., Cell 2018, 171:877-889; Li et al., Genome Biol 2018, 19:69). For example, we demonstrate that neural stem/progenitor cell (NSPC) self-renewal and spatiotemporal generation of neurons and other cell types are severely impacted by the loss of Ythdf2, a reader of m6A,  in embryonic neocortex. Despite the many novel finding on m6A dynamics in neuronal development and brain function, the understanding of regulatory mechanisms is still in its early stages.


Prof Arne Klungland is head of research at Section for Molecular Medicine at Oslo University Hospital. He did his PhD and post doctoral training with Erling Seeberg at the University of Oslo and Tomas Lindahl at Cancer research UK in London, two pioneers in the early work of DNA repair. In 2000 he had a sabbatical stay with Jean-Marc Egly at IGBMC, Strasbourgh. He started his scientific career working on DNA base excision repair (BER) and has later focused on epigenetic and epitranscriptomic regulation of  the early embryo and in the developing brain.

Prof Klungland and published more than 100 papers and has  several publications in PNAS, EMBO J, Nature Comm, Mol Cell, CELL and Nature, etc. Klungland received  the 2018 Excellent Researcher Award for Oslo University Hospital.

Will McEwan: The intracellular antibody receptor TRIM21 enables selective degradation of proteins relevant to neurodegeneration


Gene editing and RNA intereference techniques enable the selective depletion of genes at the nucleotide level. To date there are no mechanisms that enable the degradation of genes at the protein level. We identified a novel antibody receptor, TRIM21, which, uniquely among antibody receptors, is expressed in the cytoplasm. Upon encountering intracellular immune complexes, TRIM21 stimulates a rapid degradation response at the proteasome. This activity provides a last line of defence against infection during in vivo viral challenge. We recently demonstrated that TRIM21 can be repurposed against host proteins to enable the acute and selective depletion of intracellular proteins. We have developed this as a research technique, termed TrimAway, to enable broadly-applicable protein-level knockdown. The aggregation of tau is a pathological characteristic of several neurodegenerative diseases including Alzheimer’s disease. We show that assemblies of tau that act as ‘seeds’ can import antibody to the cell whereupon TRIM21 stimulates their inactivation. This provides proof-of-principle for the cytoplasmic inactivation of disease-relevant proteins in the intracellular domain.


Will McEwan studied Genetics BSc at UCL and undertook his PhD at the University of Glasgow under the supervision of Prof Brian Willett on the detection of lentivirus infection by the cytoplasmic sensor TRIM5. In 2009, he joined the lab of Dr Leo James as a postdoc at the MRC Laboratory of Molecular Biology, Cambridge, UK. Here he co-discovered TRIM21 as an antibody receptor and characterised its degradation and signalling activities (Mallery et al 2010 PNAS; McEwan et al 2012 J Virol; McEwan et al 2013 Nat Immunol). He also maintains an interest in lentivirus research contributing to the discovery of dNTP import to the HIV-1 capsid (Jacques et al 2016).

In 2017 Will McEwan was awarded a Sir Henry Dale Fellowship by the Wellcome Trust and Royal Society to extend findings that cellular proteins, including tau seeds, can be targeted by intracellular antibodies via TRIM21 (McEwan et al 2017 PNAS; Clift et al 2017 Cell). His group is hosted within the UK Dementia Research Institute at the University of Cambridge, UK.

Peter McHugh: The mechanisms of XPF-dependent DNA crosslink repair: a pathway required to suppress accelerated ageing?


The XPF and ERCC1 proteins form a heterodimeric endonuclease that plays a critical role in Nucleotide Excision Repair (NER) and also in the replication-coupled repair of DNA interstrand crosslinks (ICLs). Mutations in the XPF or ERCC1 genes cause a remarkable array of rare inherited human disorders, several associated with features of premature ageing and neurodegeneration, including Xeroderma pigmentosum, Cockayne syndrome, Fanconi anemia, and cerebro-oculo-facio-skeletal syndrome. A key, initiating event in ICL repair is incision of crosslink-arrested replication fork structures, which requires the XPF-ERCC1. Despite this, structures that model replication forks stalled by ICLs are very poor substrates for XPF-ERCC1 in vitro, indicating that additional, unidentified factors are required to target and activate this key nuclease during repair

Our recent work has demonstrated that during replication-coupled ICL repair, arrested replication fork intermediates can be processed through the dramatic stimulation of XPF-ERCC1 by both RPA and repair nuclease platform protein SLX4FANCQ, and this is likely to be critical for the repair of ICL damaged replication forks in vivo. Here, I will describe our progress towards the full biochemical reconstitution of this critical DNA repair pathway.


Peter McHugh is Professor of Molecular Oncology and Director of the Oncology Laboratories at the MRC-Weatherall Institute of Molecular Medicine. Following a a D.Phil in Biochemistry at the University of Oxford and a period of post-doctoral research at University College London, he was awarded a Royal Society University Research Fellowship in 2001. In 2003 he joined the Oncology Laboratories at the MRC Weatherall Institute of Molecular Medicine, where he heads the DNA Damage and Repair research group.

Hansang Cho: 3D Human Brain models in Microfluidics for the Study of Neurological Disorders


With hundreds of billions of neurons and thousands of trillions of synaptic connections between them, the human brain is the most complex system on earth. However, there are no well-developed human brain models to study the brain activities in either laboratory environments or in animal bodies. Here, I present micro-scaled 3D environments that reconstruct a 3D human brain in Alzheimer’s disease (AD) by recapitulating AD signature of elevated levels of amyloid-beta (A-beta), tau proteins, activation of microglia, immune cells resident in a central nervous system (CNS), and consequent neuronal damage. In particular, the model mirrored microglial neurotoxic activities such as axonal cleavage and neurotoxic release.



Dr. Cho’s research focuses on organ-on-chips, nanomedicine for the study of neurosciences and cancer biology, innovative mechanical components evolving multiple physics, and portable platforms for healthcare diagnostics and environmental sustainability. He received his B.S. and M.S in Mechanical Engineering from Seoul Nat’l University, Ph.D. in Bioengineering from University of California at Berkeley, and a postdoctoral training at Harvard Medical School. He received Cure Alzheimer’s Fund award, CRI Duke Energy Special Initiatives Funding award, Lawrence scholar program fellowship from Lawrence Livermore National Laboratory, Fellowship supported by Intel Inc., Study Abroad Scholarship by the Korean National Institute for International Education.

Dr. Cho has been productive with publications in Nature Neuroscience, Nature Communication, Nano Letters, and ACS Nano etc.

Published Apr. 8, 2019 8:39 AM - Last modified July 2, 2019 11:18 AM