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 proficiency in biophysics, structural biology, drug design, cellular biology, and animal disease models. The methodological expertise contributed to Neuro-SysMed includes target identification and compound screening utilising both biophysical and cellular screens. It includes mechanistic validation of optimal hits and comprehensive knowledge of the progression from early-stage drug discovery to the identification of best leads for proof-of-concept in patients, aiming to develop preventive and corrective therapies for Parkinson’s disease and other parkinsonian disorders.
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 world-leading 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 2024 comprised:
Mitochondrial function
In collaboration with Charalampos Tzoulis, the Drug Discovery Node has conducted a cell-based screening campaign to identify already approved drugs that can counteract the neuronal respiratory complex I (CI) deficiency observed in a subgroup of Parkinson’s disease (PD). One of the identified hit compounds by Postdoc Kunwar Jung-Kc is an FDA-approved drug with the potential to enhance mitochondrial function and that has shown promising results in enhancing mitochondrial CI protein levels and promoting mitochondrial biogenesis. Further studies are being conducted to identify the mechanisms by which the drug interacts with the cellular components to modulate mitochondrial function, with the goal of elucidating potential therapeutic effects in PD. The project has recently received additional funding from Norges Parkinson Forskningsfond to advance the drug discovery efforts, and to validate, characterise and prepare hit compounds from the drug screening to inclusion in clinical trials.
Tyrosine hydroxylase (TH) as a treatment target in PD and parkinsonisms
In a recent collaboration with the labs of Angeles García-Cazorla (Hospital Sant Joan de Déu, Barcelona) and Antonella Consiglio (Bellvitge University Hospital-IDIBELL, Barcelona), we have discovered that supplementation with the TH cofactor tetrahydrobiopterin (BH4) increases TH+ cells and DA, and improves motor outcomes in a THD mouse model, highlight the therapeutic potential of BH4 for specific TH variants and in parkinsonisms (Jung-Kc et al., 2024). Recently, the node has also identified DNAJC12 as the molecular HSP40 cochaperone that maintains TH stability and decreases its propensity to aggregate. The solved structure of the complex by Cryo-EM (Tai et al., 2024) is facilitating the discovery of stabiliser drugs of TH and the TH:DNAJC12 complex.
VMAT2 as a therapeutic target in PD
This project studies the vesicular monoamine transporter 2 (VMAT2) which is responsible for packaging monoamines such as DA 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 regulating DA signalling is not yet known. The VMAT2 project is led by Neuro-SysMed researcher Svein Isungset Støve, who has screened for compounds that modulate VMAT2 activity using both biophysical and cellular assays and has identified potent inhibitors of VMAT2 that have a potential for the treatment of Tardive Dyskinesia, as well as modulators of VMAT2 protein expression that can increase VMAT2 levels and subsequently DA sequestration. The identification of activators or stabilisers of VMAT2 is 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 key publications from 2024
- Wang X, Marmouzi I, Finnie PSB, Bucher ML, Yan Y, Williams EQ, Støve SI, Lipina TV, Ramsey AJ, Miller GW, Salahpour A. (2024) Tricyclic and tetracyclic antidepressants upregulate VMAT2 activity and rescue disease-causing VMAT2 variants. Neuropsychopharmacology. 49(11):1783-1791. doi: 10.1038/s41386-024-01914-2.
- 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. (2024) 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. 47(3):494-508. doi: 10.1002/jimd.12702.
- Thöny B, Ng J, Kurian MA, Mills P, Martinez A. (2024) Mouse models for inherited monoamine neurotransmitter disorders. J Inherit Metab Dis. 47(3):533-550. doi: 10.1002/jimd.12710.
Tai MDS, Gamiz-Arco G, Martinez A. (2024) Dopamine synthesis and transport: current and novel therapeutics for parkinsonisms. Biochem Soc Trans. 52(3):1275-1291. doi: 10.1002/jimd.12710 - Ruisch IH, Widomska J, De Witte W, Mota NR, Fanelli G, Van Gils V, Jansen WJ, Vos SJB, Fóthi A, Barta C, Berkel S, Alam KA, Martinez A, Haavik J, et al. (2024). Molecular landscape of the overlap between Alzheimer's disease and somatic insulin-related diseases. Alzheimers Res Ther. 16(1):239. doi: 10.1186/s13195-024-01609-2.
- Tai MDS, Ochoa L, Flydal M, Velasco-Carnero L, Muntaner J, Santiago C, Gamiz-Arco G, , Moro F, Jung-Kc K, Gil-Cantero D, Marcilla M, Kallio J, Muga A, Valpuesta JM, Cuellar J, Martinez A (2025). Structural recognition and stabilization of tyrosine hydroxylase by the J-domain protein DNAJC12. Nat Commun. In Press.