Improved monitoring and treatment of neurometabolic disorders

Highlights 2021

Neuropsychiatric comorbidities are common for metabolic disorders. In many cases this can be linked to disturbances in one or several neurotransmitters. The MEDIATE project is concerned with mechanisms underlying disturbed monoamine neurotransmission and homeostasis in disorders of amino acid metabolism.

During 2021 we have made progress on mathematical modelling of homeostasis regulation in the dopamine pathway (1) and, together with collaborators in Spain, on the structural mechanism for the interplay between allosteric and signaling regulation of dopamine homeostasis (2). Using drug screening, we have also identified a potent antioxidant, ebselen, as a disruptor of regulatory hub proteins that are also modulators of enzymes in the monoamine synthesis (3). The biological implication of this discovery is yet unclear, but this could have implications for the clinical use of such compounds and for targeting oxidative stress in metabolic disorders. Ebselen is under clinical trial for COVID-19, biopolar disorder and acute ischemic stroke.

Other publication highlights of 2021 were two reviews by the project consortium; one where the presence of ADHD-like symptoms in a range of metabolic diseases was emphasized (4) and one study underlining the value of biochemical, cellular and mathematical modeling in a personalized medicine approach to improve treatment of dopa responsive dystonia (5).

Unfortunately, the pandemic has continued to affect the project during 2021 - influencing also collaborative efforts and participation within the DLN. However, we are very happy to have initiated a collaboration on metabolomics with the AurOmega project. We were also happy to participate on the DLN annual conference and will now pursue a collaboration with 3DLife on neuronal cell culture modeling as a result of this.

1) Kleppe et al. PMID: 34884667

2) Bueno-Carrasco et al. PMID: 35013193

3) Waløen et al. PMID: 34031189

4) Cannon Homaei et al. PMID: 34774900

5) Nygaard et al. PMID: 34834538

Scientific publications 2021: 5

Project overview

Project lead: Jan Haavik
Institution: University of Bergen/Haukeland University Hospital
Partners: Oslo University Hospital (Rikshospitalet), University of Stavanger
Funding: Regional Health Authorities of Western Norway

Research group

Researchers at The Neurotargeting Research Group in Bergen are working to understand possible links between some metabolic and psychiatric disorders. Correctly identifying and treating the root metabolic cause of these neurometabolic disorders early can save someone from disability or even death. 

Today, there are no laboratory tests to help physicians understand the underlying causes of psychiatric symptoms, and most of the limited treatments available for these patients are more than 50 years old.

The scientific literature contains many examples of metabolic diseases causing psychiatric symptoms like depression, hyperactivity, and psychosis. The Neurotargeting Research Group’s lead, Professor Jan Haavik, a practicing psychiatrist with a PhD in biochemistry, thinks that understanding the underlying biological mechanisms of these disorders might be the key to identifying and treating them in patients. For example, The Neurotargeting Research Group is studying is tyrosinemia, a genetic neurometabolic disorder that results in a buildup of the amino acid tyrosine which interferes with signaling pathways in the brain and can present clinically as ADHD. 

In order to better understand the neurological and metabolic connection in the tyrosinemia, the research group wants to find out how variations in the genetic mutations that cause the disorder result in different clinical presentations. 

The researchers have collected clinical and biological data from all Norwegian children who have tyrosinemia. They invite patients and their families to take part in clinical examinations to determine their phenotype and then correlate that information with biological samples (blood and saliva) from biobanks. Combining techniques from the fields of metabolomics, psychiatry, structural biology, and proteomics, they are also working to identify the underlying cause of tyrosinemia and other neurometabolic disorders. Their goal is to give physicians new tools to identify the underlying causes of these disorders and treat their patients.

It is difficult to study the live human brain and many of these neurometabolic disorders are rare conditions. To overcome the challenges of working with small sample population sizes, the research group will share their data with the global consortium of omics researchers. Finding correlations in small sample sizes requires a global interdisciplinary effort. The researchers are also working with patient organizations to protect the vulnerable patients they are studying and all the released data will be compliant with responsible research and innovation (RRI) best practices. This is a long-term project that will provide biological insights into psychiatric and metabolic disorders and expand physicians’ ability to care for their patients. 

By Matthew Davidson

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