Digital Public Defence: Margrete Langmyhr

MSc Margrete Langmyhr at Institute of Clinical Medicine will be defending the thesis "Investigating the molecular genetics of sporadic Parkinson’s disease" for the degree of PhD (Philosophiae Doctor).

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Photo: Tom Emrich-Mills

The public defence will be held as a video conference over Zoom.

The defence will follow regular procedure as far as possible, hence it will be open to the public and the audience can ask ex auditorio questions when invited to do so.

Click here to participate in the public defence

Download Zoom here

Due to copyright reasons, an electronic copy of the thesis must be ordered from the faculty. In order for the faculty to have time to process the order, it must be received by the faculty no later than 2 days prior to the public defence. Orders received later than 2 days before the defence will not be processed. Inquiries regarding the thesis after the public defence must be addressed to the candidate.

Order a digital copy of the thesis here

 

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Adjudication committee

  • First opponent: Research Group Leader Joanne Trinh, Institute of Neurogenetics, University of Lübeck, Germany
  • Second opponent: Clinical Associate Professor Christos Proukakis, University College London, Queen Square Institute of Neurology, UK
  • Third member and chair of the evaluation committee: Professor Eirik Frengen, Institute of Clinical Medicine, University of Oslo

Chair of defence

Professor II Bjørnar Hassel, Institute of Clinical Medicine, University of Oslo

Principal Supervisor

Professor II Mathias Toft, Institute of Clinical Medicine, University of Oslo

Summary

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder worldwide. The disease is characterized by the loss of dopaminergic neurons of the midbrain and the presence of Lewy pathology: abnormal filamentous aggregates containing α-synuclein, a protein encoded by the SNCA gene. There are currently no treatments available that target the cause of PD or alter the progressive course of neurodegeneration. A deeper understanding of the molecular mechanisms involved in disease development is therefore pivotal to develop novel disease-modifying therapies.

Genome-wide association studies (GWAS) have identified 90 genetic risk variants for PD that represent key tools in the effort to understand the genetic component of sporadic disease. This doctoral thesis connects genetic variants from PD-associated GWAS loci to gene expression patterns, thus revealing the allelic expression of genes in human brain samples. We found allele-specific expression in most of the investigated PD-associated genes, suggesting that these genetic variants are found in regulatory elements and function as expression quantitative trait loci. Moreover, we investigated the functional effects of the most statistically significant genetic variant: rs356182 at the SNCA locus. Our results showed that rs356182 is located in a neuron-specific cis-regulatory element that is modulated in an allele-specific manner.

Finally, we provide evidence against recent reports that β2-adrenoreceptor agonists act as potential therapies for PD through the downregulation of SNCA expression. Importantly, we revealed a lack of the β2-adrenoreceptor in disease-affected brain regions. Moreover, dopaminergic neuron-like cells treated with β2-adrenoreceptor agonists and antagonists did not in fact show altered SNCA expression levels.
Collectively, the studies presented herein employ modern techniques to help expand the understanding of PD genetic risk factors, in particular those affecting SNCA expression.

Additional information

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Published Nov. 23, 2021 1:58 PM - Last modified Nov. 26, 2021 1:19 PM