Improved monitoring and treatment of neurometabolic disorders

Highlights 2020

The project's contribution to the Centre for Digital Life Norway annual report 2020.

In the MEDIATE project we seek to understand how metabolic disorders that affect amino acid metabolism disturb neurotransmission and monoamine neurotransmitter homeostasis. This can result in neuropsychiatric symptoms that are often ignored, as they fall in the shadow of life-saving treatments or more dominating somatic symptoms of these rare disorders.

During 2020 we established several model systems to investigate cell signalling and redox responses to abnormal amino acid levels. We also elucidated a structural basis for regulating catecholamine synthesis through allosteric and signalling mechanisms. In the kinetic modelling activity, we have begun to analyse homeostatic mechanisms in presynaptic dopamine synthesis and to investigate existing mathematical models. The project has recruited new personnel and a PhD student that is investigating the synthesis of redox active carnosine dipeptides, using a newly established mouse model.

A highlight during 2020 was the publication resulting from the development of this mouse model (1), showing the importance of a newly characterised enzyme in the synthesis of carnosine. Another publication highlight was a study led by our partners in Barcelona on the regulatory 14-3-3 proteins in autism spectrum disorders and schizophrenia (2). These proteins are known to regulate monoamine homeostasis and metabolism and we are now investigating possible ways to target their functions. Some of these findings were communicated in a blog post on the DLN web page (3).

Despite the interesting welcome meeting for new projects just before the COVID-19 pandemic hit us, the year 2020 has been challenging, especially in terms of having physical meetings and establishing new collaborations within the centre. We hope to pursue these opportunities when the situation improves, and we have identified several interesting follow-up projects and activities. The new PhD student is happy to be part of the research school and hopes to meet with fellow members in the near future!

  1. Mahootchi et al. GADL1 is a multifunctional decarboxylase with tissue-specific roles in β-alanine and carnosine production. Sci Adv. 2020 Jul 17;6(29):eabb3713. doi: 10.1126/sciadv.abb3713.
  2. Torrico et al. Involvement of the 14-3-3 Gene Family in Autism Spectrum Disorder and Schizophrenia: Genetics, Transcriptomics and Functional Analyses. J Clin Med. 2020 Jun 13;9(6):1851. doi: 10.3390/jcm9061851.
  3. Blog post June 16: Neurotransmitter alterations in metabolic and psychiatric disorders

Scientific publications 2020: 4

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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