Project ID NS-MH2026_58

ThemeNS-MH

Co Supervisor 1A Dr Karin Tuschl Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, Institute of Pharmaceutical ScienceEmail

Co Supervisor 1B Dr Cinzia Imberti Faculty of Life Sciences & Medicine, School of Biomedical Engineering & Imaging Sciences, Department of Imaging Chemistry & BiologyEmail

Advancing Treatment Strategies for Manganese-Related Neurodegeneration

Scientific background

Inherited manganese transporter defects (HMNDYT1/2), caused by mutations in SLC30A10 and SLC39A14, lead to brain manganese accumulation, severe neurodisability, and premature death. Current treatment with intravenous Na₂CaEDTA is burdensome, requiring monthly hospitalisation and offering limited efficacy. More effective, patient-friendly therapies are urgently needed.

We are developing two novel therapeutic approaches: (1) JD156, a manganese-selective chelator with 1,000-fold higher binding affinity than Na₂CaEDTA, and (2) lipid nanoparticle (LNP)-encapsulated SLC30A10 mRNA.

To advance clinical translation, we need to confirm therapeutic efficacy and establish a blood-based biomarker assay to monitor treatment response.

Techniques and skills to be developed

52Mn positron emission tomography (PET), mass spectrometry (MS) approaches; bioinformatic analysis of omics data; mouse husbandry and manipulation; immunohistochemistry, confocal imaging; molecular biology.

Aims of the project

This multidisciplinary project aims to advance our understanding of the molecular mechanisms underlying manganese neurotoxicity and improve therapeutic strategies.

Objectives

Year 1-3: Confirm rescue of manganese kinetics using PET.
We have already shown that manganese flux is impaired in Slc30a10KO/KO mice. Using 52Mn-PET the student will determine whether JD156/LNP-mRNA can normalise in vivo manganese kinetics. In parallel, the extent of organ delivery of JD156/LNP-mRNA can be assessed.

Year 1: Identify proteomic and lipidomic biomarkers for HMNDYT1/2.
In collaboration with the UCL GOS ICH-Biological Mass Spectrometry Centre, the student will perform untargeted proteomics and targeted lipidomics on
1. Dried blood spots from patients with HMNDYT1/2.
2. Brains from Slc30a10KO/KO mice untreated and treated with JD156/LNP-mRNA.

Year 2-3: Develop and validate a targeted biomarker assay in patient blood spots.
A selection of biomarkers will be made and a targeted LC-MS/MS assay in dried blood spots developed. This will be validated in treated Slc30a10KO/KO mice, comparing assay results with tissue manganese, haemoglobin, and histopathology.

Year 4: Identify novel regulators/effectors of manganese homeostasis/neurotoxicity.
Proteomic and lipidomic changes are expected to elucidate molecular pathways of manganese neurotoxicity. In the final year, the student will be able to interrogate molecular targets using e.g. immunohistochemistry, Western blotting, CRISPR/Cas9 etc.

Thus, this work opens an avenue for translational research including identification of new therapeutic targets, biomarkers and novel therapies for metal transport disorders.

Rotation project

Using existing proteomic and transcriptomic data from Slc30a10KO/KO mice, the student will validate novel manganese homeostasis or neurotoxicity candidates via qPCR, Western blotting and immunohistochemistry. This will lay the foundation for the PhD project by allowing the student to familiarise themselves with existing omics data and acquire key project-specific skills.

Representative Publications

• Tuschl K, White RJ, Trivedi C, Valdivia LE, Niklaus S, Bianco IH, Dadswell C, González-Méndez R, Sealy IM, Neuhauss SCF, Houart C, Rihel J, Wilson SW, Busch-Nentwich EM. Loss of slc39a14 causes simultaneous manganese hypersensitivity and deficiency in zebrafish. Dis Model Mech. 2022 Jun 1;15(6):dmm044594. doi: 10.1242/dmm.044594. • Tuschl K, Meyer E, Valdivia LE, Zhao N, Dadswell C, Abdul-Sada A, Hung CY, Simpson MA, Chong WK, Jacques TS, Woltjer RL, Eaton S, Gregory A, Sanford L, Kara E, Houlden H, Cuno SM, Prokisch H, Valletta L, Tiranti V, Younis R, Maher ER, Spencer J, Straatman-Iwanowska A, Gissen P, Selim LA, Pintos-Morell G, Coroleu-Lletget W, Mohammad SS, Yoganathan S, Dale RC, Thomas M, Rihel J, Bodamer OA, Enns CA, Hayflick SJ, Clayton PT, Mills PB, Kurian MA, Wilson SW. Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia. Nat Commun. 2016 May 27;7:11601. doi: 10.1038/ncomms11601. • Tuschl K, Clayton PT, Gospe SM Jr, Gulab S, Ibrahim S, Singhi P, Aulakh R, Ribeiro RT, Barsottini OG, Zaki MS, Del Rosario ML, Dyack S, Price V, Rideout A, Gordon K, Wevers RA, Chong WK, Mills PB. Syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia caused by mutations in SLC30A10, a manganese transporter in man. Am J Hum Genet. 2012 Mar 9;90(3):457-66. doi: 10.1016/j.ajhg.2012.01.018.

“• Imberti C, De Gregorio R, Korsen JA, Hoang TT, Khitrov S, Kalidindi T, Nandakumar S, Park J, Zaidi S, Pillarsetty NVK, Lewis JS. CEACAM5-Targeted Immuno-PET in Androgen Receptor-Negative Prostate Cancer. J Nucl Med. 2024 Jul 1;65(7):1043-1050. doi: 10.2967/jnumed.123.267107. • Imberti C, Lok J, Coverdale JPC, Carter OWL, Fry ME, Postings ML, Kim J, Firth G, Blower PJ, Sadler PJ. Radiometal-Labeled Photoactivatable Pt(IV) Anticancer Complex for Theranostic Phototherapy. Inorg Chem. 2023 Dec 18;62(50):20745-20753. doi: 10.1021/acs.inorgchem.3c02245. • Imberti C, Adumeau P, Blower JE, Al Salemee F, Baguña Torres J, Lewis JS, Zeglis BM, Terry SYA, Blower PJ. Manipulating the In Vivo Behaviour of 68Ga with Tris(Hydroxypyridinone) Chelators: Pretargeting and Blood Clearance. Int J Mol Sci. 2020 Feb 22;21(4):1496. doi: 10.3390/ijms21041496.”