A key focus in the lab is studies of proteins involved in dopamine synthesis and transport. The projects combine biochemical, biophysical and structural studies of isolated proteins and protein complexes with assays in cellular and animal models, elucidating the pathogenic role of dysfunctional biomolecular interactions and loss of protein stability on genotypecorrelations and gain-of-function comorbidities. The group is also increasing its research- and innovation focus on drug discovery and development, and contributes to Nor-Openscreen and EU-Openscreen
(Eric and Drive) infrastructure projects for highcapacity screening, chemical biology and drug design, focusing on low molecular weight drug candidates (figure 1). Furthermore, the Martinez lab investigates the characterization and optimization of interactions with selected proteins, notably tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of dopamine, for enzyme stabilization and improved cellular uptake, aiming at development of enzyme replacement therapies (see key publications to the right).
Within the Neuro-SysMed centre, the research of the group is integrated in translational projects with clinical partner groups, focusing on molecular mechanisms involved in the development and progression of Parkinson’s disease, and on the concomitant discovery and evaluation of specific mechanistic-based therapies. The use of highthroughput screening methods and facilities are essential in these projects. Towards this end, the Martinez lab has initiated projects to understand and develop therapies to correct (i) dysfunctional proteinprotein interactions involved in dopamine synthesis and vesicular transport, (ii) proteostasis dysregulation, and (iii) neuronal respiratory complex I deficiency and impaired mitochondrial DNA homeostasis, collaborating with Neuro-SysMed partners Trond Riise, Charalampos Tzoulis and Laurence A. Bindoff.
Selected Key Publications
1. Aubi O, Prestegård KS, Jung-KC K, Shi TS, Ying M, Grindheim AK, Scherer T, Ulvik A, McCann A, Spriet E, Thöny B, Martinez A (2021). The Pah-R261Q mouse reveals oxidative stress associated with amyloid-like hepatic aggregation of mutant phenylalanine hydroxylase. Nat. Commun. DOI: 10.1038/s41467-021-22107-1
2. Bezem MT, Johannessen FG, Kråkenes TA, Sailor MJ, Martinez A. (2021) Relevance of electrostatics for the interaction of tyrosine hydroxylase with porous silicon nanoparticles. Mol Pharm. 18:976-985. DOI: 10.1021/acs.molpharmaceut.0c00960.
3. Flydal MI, Kråkenes TA, Tai MDS, Tran MPA, Teigen K, Martinez A. (2020) Levalbuterol lowers the feedback inhibition by dopamine and delays misfolding and aggregation in tyrosine hydroxylase. Biochimie S0300-9084(20)30322-9. DOI: 10.1016/j.biochi.2020.12.002.
4. Støve SI, Flydal MI, Hausvik E, Underhaug J, Martinez A. Chapter 15 – Differential scanning fluorimetry in the screening and validation of pharmacological chaperones for soluble and membrane proteins. In: Protein Homeostasis Diseases (ed Pey AL). Academic Press (2020). https://doi.org/10.1016/B978-0-12-819132-3.00015-4