Drug discovery-noden

Node leaders: Aurora Martinez and Trond Riise

Aurora Martinez is a professor at the Department of Biomedicine, University of Bergen, and the head of the Biorecognition group. The research group investigates the molecular mechanisms underlying neurometabolic and neurological disorders applying multidisciplinary and translational approaches. The Martinez Lab is a specialised screening site at the NOR-Openscreen and EU-Openscreen networks and has skills in biophysics, structural biology, drug design, cellular biology, and animal models of disease. The methodological expertise brought to Neuro-SysMed includes target identification and compound screening using both biophysical and cellular screens, mechanistic validation of best hits and knowledge on the path from early-stage drug discovery to the identification of best leads towards proof-of-concept in patients, aiming to develop preventive and corrective therapies for Parkinson’s disease and other parkinsonisms.

Trond Riise is a professor in epidemiology at the University of Bergen. He leads the DRONE group – Drug RepurpOsing for NEurological diseases. The DRONE group harbours worldleading expertise on registry and epidemiology research. They focus on virtual drug screening, employing the Norwegian national registries to identify candidate drugs for repurposing. Riise’s research is related to epidemiological studies of neurological diseases including Parkinson’s disease and multiple sclerosis. The focus is to identify environmental factors that, on their own or in combinations, significantly change the disease risk.

Node activities

The activities of the Drug Discovery Node in 2023 comprised:

• Mitochondrial function. The Drug Discovery Node is optimising screening approaches and assays targeting neuronal respiratory complex I (CI) deficiency and impaired mitochondrial DNA homeostasis, in collaboration with Professor Charalampos Tzoulis. They have established a cell-based screening method and are currently screening libraries, predominantly for drug repurposing. In 2023 they identified an FDAapproved drug with the previously unknown potential to enhance mitochondrial CI protein levels and increase mitochondrial biogenesis. Further investigation is being conducted to identify the mechanisms through which the drug interacts with the cellular components to modulate mitochondrial function, aiming to elucidate the potential therapeutic effects in various disease conditions, such as PD.
  
  
• Tyrosine hydroxylase (TH) as a treatment target in PD and parkinsonisms. In collaboration with the labs of Angeles García-Cazorla (Hospital Sant Joan de Déu, Barcelona) and Antonella Consiglio (Bellvitge University Hospital-IDIBELL, Barcelona), the node has recently investigated alternative therapeutic options for patients with TH deficiency (THD), a rare disorder associated with parkinsonism and variable response to L-Dopa treatment. Using dopamine-neurons differentiated from iPSCs from healthy subjects and THD patients, they found that supplementation of the TH cofactor tetrahydrobiopterin (BH4) resulted in an increase in the number of TH+ cells and improved motor outcomes in a knock-in THD mouse model. These findings highlight the therapeutic potential of BH4 for specific TH variants (Jung-Kc et al., 2024).
  
  
• The node has also continued their work on the identification of drugs that maintain the proteostatic regulation and intracellular stability of TH. They have recently identified DNAJC12 as a molecular chaperone that maintains the stability of TH and decreases its propensity to aggregate, especially in the case of THD-associated variants. The recently solved structure of the complex by Cryo-EM (Tai et al., 2023; preprint; https://doi.org/10.21203/rs.3.rs-3621320/v1) is facilitating the screening and derivatisation of stabiliser drugs of TH and the TH:DNAJC12 complex.
  
  
• VMAT2 as a treatment target in PD. This project studies the vesicular monoamine transporter 2 (VMAT2) which is responsible for packaging of monoamines such as dopamine into synaptic vesicles for subsequent release into the synaptic cleft. VMAT2 is associated with both TH and α-synuclein, both important targets in PD, but the role of this association in regulation of DA signalling is still not known. In a recent project, Neuro-SysMed researcher Svein Isungset Støve has screened for compounds modulating VMAT2 activity using both biophysical and cellular screenings and has obtained effective inhibitors of VMAT2 that have a potential for treatment of Tardive Dyskinesia. He continues the project in a screening campaign to identify molecular chaperones that can increase VMAT2 expression levels and subsequently dopamine sequestration. The identification of activators or stabilisers of VMAT2 is especially interesting, as high cytoplasmic levels of DA are associated with cytotoxicity, and stimulation of VMAT2 in early stages of PD is a therapeutic approach of increasing interest.
  
  
• Registry-based drug screening. Riise’s group is conducting a comprehensive registry-based drug screening project which involves screening of all prescriptions given to all Norwegians since 2004. These prescriptions (about 800 mill) are linked to the incidence of Parkinson’s disease (PD), amyotrophic
  lateral sclerosis (ALS) and multiple sclerosis (MS). The overall objective of the project is to evaluate whether existing drugs (molecules) can be repurposed as effective treatment of PD, ALS and MS. A full screen of drugs associated with PD-risk has been completed, and in collaboration with Clemens Scherzer, director of The Neurogenomics Lab at Harvard University, the groups is currently validating 72 promising drugs using neurons from patient stem cells carrying the SNCA triplication linked to autosomal dominant PD. The first epi-screening results are published in Neurology (2023, Romanowska et. al.).
  The group has further received new funding from the Michael J. Fox Foundation (USD 300 K) to combine their results with similar studies in Finland and France using meta-analysis.

Selected publications from 2023:

1. Jung-Kc K, Tristán-Noguero A, Altankhuyag A, Piñol Belenguer D, Prestegård KS, Fernandez-Carasa I, Colini Baldeschi A, Sigatulina Bondarenko M, García-Cazorla A, Consiglio A, Martinez A. Tetrahydrobiopterin (BH4) treatment stabilizes tyrosine hydroxylase: Rescue of tyrosine hydroxylase deficiency phenotypes in human neurons and in a knock-in mouse model. J Inherit Metab Dis. 2024 Jan 9. doi:10.1002/jimd.12702. PMID: 38196161.
2. Thöny B, Ng J, Kurian MA, Mills P, Martinez A. Mouse models for inherited monoamine neurotransmitter disorders. J Inherit Metab Dis. 2024 Jan 2. doi: 10.1002/jimd.12710. PMID: 38168036.
3. Alam KA, Svalastoga P, Martinez A, Glennon JC, Haavik J. Potassium channels in behavioral brain disorders. Molecular mechanisms and therapeutic potential: A narrative review. Neurosci Biobehav Rev. 2023 152:105301. doi: 10.1016/j.neubiorev.2023.105301. PMID: 37414376.
4. Romanowska J, Bjornevik K, Cortese M, Tuominen JA, Solheim M, Abolpour Mofrad A, Igland J, Scherzer CR, Riise T. Association Between Use of Any of the Drugs Prescribed in Norway and the Subsequent Risk of Parkinson Disease: A Drug-wide Association Study. Neurology. 2023 Nov 21;101(21):e2068-e2077. doi:10.1212/WNL.0000000000207899. Epub 2023 Oct 10. PMID: 37816645.
5. Tuominen JA, Bjørnevik K, Romanowska J, Solheim MH, Grydeland TB, Cortese M, Scherzer CR, Riise T, Igland J. Beta2-adrenoreceptor agonists and long-term risk of Parkinson's disease. Parkinsonism Relat Disord. 2023 May;110:105389. doi: 10.1016/j.parkreldis.2023.105389. Epub 2023 Mar 31. PMID: 37027994.
6. Olsen A, Locascio J, Tuncali I, Laroussi N, Abatzis E, Kamenskaya P, Kuras Y, Yi T, Videnovic A, Hayes M, Ho G, Paulson J, Khurana V, Herrington T, Hyman B, Selkoe D, Growdon J, Gomperts S, Riise T, Schwarzschild M, Hung A, Wills A, Scherzer C. Health phenome of Parkinson's patients reveals prominent mood-sleep cluster. Res Sq. 2023 Dec 22:rs.3.rs-3683455. doi: 10.21203/rs.3.rs-3683455/v1. Preprint. PMID: 38196602
7. Riise T, Solheim M, Bjornevik K, Igland J, Tuominen J, Mofrad A, Cortese M, Scherzer C, Romanowska J. Treatment of High Blood Pressure is associated
   with a Reduced Incidence of Parkinson's disease. Neurology 2023 April 25, 100 (suppl 2). doi.org/10.1212/WNL.0000000000202952.