Elucidating the role of manganese in brain physiology and disease
Lead Research Organisation:
University College London
Department Name: Institute of Child Health
Abstract
i) Background
Manganese (Mn) is an essential trace metal in our diet that is required for normal brain function. However, exposure to high Mn concentrations causes brain damage and a debilitating movement disorder similar to Parkinson's disease. Mn toxicity, also known as manganism, occurs in children and adults upon environmental and occupational overexposure due to contaminated drinking water and drug formulations, industrial fumes or intravenous nutrition, and in patients with liver damage. The recent identification of inherited disorders of Mn transport due to abnormalities in the genes SLC30A10, SLC39A14 and SLC39A8 has further highlighted the important influence Mn has on brain physiology. These disorders lead to impaired control of the body's Mn load, resulting in Mn overload or deficiency, and are associated with detrimental neurodevelopmental disorders of childhood. There is increasing evidence that Mn imbalance is also a feature of common neurodegenerative disorders including Parkinson, Alzheimer and Huntington disease.
Our understanding of how Mn imbalance leads to disease is poor and treatments to alleviate neurological symptoms for the above conditions remain unsatisfactory. Currently available therapies to lower Mn levels are extremely burdensome due to frequent intravenous administration requiring life-long, monthly hospital admissions, venous access related complications and medication side effects. Therefore, there is a great need for research in this field.
ii) Aims of my research
This fellowship intends to establish the role of Mn in normal brain function and to understand how Mn imbalance disturbs the physiological processes within nerve cells. Thereby, my work aims to identify novel therapeutic targets and improve treatments for Mn related disease. This will be accomplished through the study of established and validated genetically modified zebrafish as models for the human Mn transporter disorders. Zebrafish are ideally suited for the study of neurological processes as their nervous system is structurally and chemically similar to that of humans whilst also transparent allowing brain imaging while alive.
First, I will determine which nerve cells are affected by Mn overload and deficiency through analysis of brain activity, anatomy and neuronal function. To better understand the effects of Mn imbalance I will generate cell culture models of the specific neuronal cells targeted by Mn. This will allow me to study the effect of Mn on energy metabolism, free radicals and cellular stress with a view to identifying the key events caused by Mn imbalance.
My previous work has identified a novel Mn binding drug that effectively lowers Mn levels and normalises swimming activity in a zebrafish model of Mn toxicity. This and other compounds will be tested biochemically and in a mouse model of Mn overload in order to develop a suitable paediatric formulation for further preclinical studies beyond this fellowship.
The project will be carried out by myself, a scientist with extensive expertise in Mn and zebrafish research, as well as a postdoctoral researcher with significant experience in mouse laboratory skills. A unique set of collaborators will share world-class expertise on zebrafish and mouse neuroscience, cell biology, paediatric drug development and chemistry ensuring translational relevance.
iii) Expected benefit
This fellowship will provide a better understanding of how Mn imbalance is involved in the disease processes underlying inherited and acquired disorders associated with Mn associated brain damage. This will allow the development of effective treatments to halt disease progression and reduce disability and mortality in children and adults suffering from these disorders. Identification of the role of Mn in neurodegenerative disease processes may also shed new light on the disease mechanisms underlying common neurodegenerative disorders such as Parkinson's disease.
Manganese (Mn) is an essential trace metal in our diet that is required for normal brain function. However, exposure to high Mn concentrations causes brain damage and a debilitating movement disorder similar to Parkinson's disease. Mn toxicity, also known as manganism, occurs in children and adults upon environmental and occupational overexposure due to contaminated drinking water and drug formulations, industrial fumes or intravenous nutrition, and in patients with liver damage. The recent identification of inherited disorders of Mn transport due to abnormalities in the genes SLC30A10, SLC39A14 and SLC39A8 has further highlighted the important influence Mn has on brain physiology. These disorders lead to impaired control of the body's Mn load, resulting in Mn overload or deficiency, and are associated with detrimental neurodevelopmental disorders of childhood. There is increasing evidence that Mn imbalance is also a feature of common neurodegenerative disorders including Parkinson, Alzheimer and Huntington disease.
Our understanding of how Mn imbalance leads to disease is poor and treatments to alleviate neurological symptoms for the above conditions remain unsatisfactory. Currently available therapies to lower Mn levels are extremely burdensome due to frequent intravenous administration requiring life-long, monthly hospital admissions, venous access related complications and medication side effects. Therefore, there is a great need for research in this field.
ii) Aims of my research
This fellowship intends to establish the role of Mn in normal brain function and to understand how Mn imbalance disturbs the physiological processes within nerve cells. Thereby, my work aims to identify novel therapeutic targets and improve treatments for Mn related disease. This will be accomplished through the study of established and validated genetically modified zebrafish as models for the human Mn transporter disorders. Zebrafish are ideally suited for the study of neurological processes as their nervous system is structurally and chemically similar to that of humans whilst also transparent allowing brain imaging while alive.
First, I will determine which nerve cells are affected by Mn overload and deficiency through analysis of brain activity, anatomy and neuronal function. To better understand the effects of Mn imbalance I will generate cell culture models of the specific neuronal cells targeted by Mn. This will allow me to study the effect of Mn on energy metabolism, free radicals and cellular stress with a view to identifying the key events caused by Mn imbalance.
My previous work has identified a novel Mn binding drug that effectively lowers Mn levels and normalises swimming activity in a zebrafish model of Mn toxicity. This and other compounds will be tested biochemically and in a mouse model of Mn overload in order to develop a suitable paediatric formulation for further preclinical studies beyond this fellowship.
The project will be carried out by myself, a scientist with extensive expertise in Mn and zebrafish research, as well as a postdoctoral researcher with significant experience in mouse laboratory skills. A unique set of collaborators will share world-class expertise on zebrafish and mouse neuroscience, cell biology, paediatric drug development and chemistry ensuring translational relevance.
iii) Expected benefit
This fellowship will provide a better understanding of how Mn imbalance is involved in the disease processes underlying inherited and acquired disorders associated with Mn associated brain damage. This will allow the development of effective treatments to halt disease progression and reduce disability and mortality in children and adults suffering from these disorders. Identification of the role of Mn in neurodegenerative disease processes may also shed new light on the disease mechanisms underlying common neurodegenerative disorders such as Parkinson's disease.
Technical Summary
Aim:
My work aims to establish the role of manganese (Mn) in neuronal physiology and disease with the view to identify novel therapeutic targets and treatments for Mn related disorders.
Objectives:
1. Determine how Mn dyshomeostasis impairs brain activity and identify the neuronal subtypes affected by Mn imbalance.
2. Identify key molecular targets underlying Mn dyshomeostasis and elucidate hierarchical interactions between them.
3. Develop a Mn specific chelator with oral bioavailability that can reverse Mn neurotoxicity.
Methodologies:
1. Study of Mn transporter mutant zebrafish (slc39a14-/- and slc39a8-/-) as models of Mn overload and deficiency: Whole-brain neuronal activity, neuroanatomy and neurochemistry mapping, in vivo calcium imaging, retinal immunohistochemistry, LA-ICP-MS, single-cell RNA sequencing and CRISPR/Cas9 genome editing.
2. Subtype-specific neuronal cultures from mutant zebrafish using FAC sorting of transgenic lines: study of the effect of Mn on cell biology (neuronal morphology, cytotoxicity, Mn distribution, Ca2+ homeostasis, oxidative stress, mitochondrial physiology, bulk RNA sequencing). Complementary in vivo analysis of mutant zebrafish using fluorescent probes, transgenic lines, and pathway inhibitors to assess their effect on the locomotor phenotype.
3. Preformulation studies of Mn chelators and prodrugs to design clinically relevant formulations. Neuropathological and behavioural characterisation of Slc30a10-/- mice to develop phenotypic readouts of Mn neurotoxicity and assessing the effects of compounds with suitable physiochemical and biopharmaceutical properties on neurological markers.
Scientific and medical opportunities:
This work will provide a clear understanding of the effects of Mn dyshomeostasis on key neuronal functions and its role in disease processes. The data on novel Mn ligands will be essential for the translation into preclinical studies and clinical trials.
My work aims to establish the role of manganese (Mn) in neuronal physiology and disease with the view to identify novel therapeutic targets and treatments for Mn related disorders.
Objectives:
1. Determine how Mn dyshomeostasis impairs brain activity and identify the neuronal subtypes affected by Mn imbalance.
2. Identify key molecular targets underlying Mn dyshomeostasis and elucidate hierarchical interactions between them.
3. Develop a Mn specific chelator with oral bioavailability that can reverse Mn neurotoxicity.
Methodologies:
1. Study of Mn transporter mutant zebrafish (slc39a14-/- and slc39a8-/-) as models of Mn overload and deficiency: Whole-brain neuronal activity, neuroanatomy and neurochemistry mapping, in vivo calcium imaging, retinal immunohistochemistry, LA-ICP-MS, single-cell RNA sequencing and CRISPR/Cas9 genome editing.
2. Subtype-specific neuronal cultures from mutant zebrafish using FAC sorting of transgenic lines: study of the effect of Mn on cell biology (neuronal morphology, cytotoxicity, Mn distribution, Ca2+ homeostasis, oxidative stress, mitochondrial physiology, bulk RNA sequencing). Complementary in vivo analysis of mutant zebrafish using fluorescent probes, transgenic lines, and pathway inhibitors to assess their effect on the locomotor phenotype.
3. Preformulation studies of Mn chelators and prodrugs to design clinically relevant formulations. Neuropathological and behavioural characterisation of Slc30a10-/- mice to develop phenotypic readouts of Mn neurotoxicity and assessing the effects of compounds with suitable physiochemical and biopharmaceutical properties on neurological markers.
Scientific and medical opportunities:
This work will provide a clear understanding of the effects of Mn dyshomeostasis on key neuronal functions and its role in disease processes. The data on novel Mn ligands will be essential for the translation into preclinical studies and clinical trials.
Organisations
- University College London (Fellow, Lead Research Organisation)
- University of Sussex (Collaboration)
- University College London (Collaboration)
- Medical University of Vienna (Collaboration)
- University of Sheffield (Collaboration)
- University of Zurich (Collaboration)
- CeMM Research Center for Molecular Medicine (Collaboration)
- Brown University (Collaboration)
- Penn State University (Collaboration)
- Cornell University (Collaboration)
- The Wellcome Trust Sanger Institute (Collaboration)
- KING'S COLLEGE LONDON (Collaboration)
People |
ORCID iD |
Karin Tuschl (Principal Investigator / Fellow) |
Publications
Alba-González A
(2024)
Manganese Overexposure Alters Neurogranin Expression and Causes Behavioral Deficits in Larval Zebrafish
in International Journal of Molecular Sciences
Gurung S
(2023)
The incidence of movement disorder increases with age and contrasts with subtle and limited neuroimaging abnormalities in argininosuccinic aciduria
in Journal of Inherited Metabolic Disease
Tuschl K
(2022)
Loss of slc39a14 causes simultaneous manganese hypersensitivity and deficiency in zebrafish.
in Disease models & mechanisms
Description | International consensus recommendations for the diagnosis and management of hypermanganesaemia with dystonia (HMNDYT) |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Participation in a guidance/advisory committee |
Description | NIHR GOSH BRC Junior Faculty Consumable Call |
Amount | £10,000 (GBP) |
Organisation | Great Ormond Street Hospital (GOSH) |
Sector | Hospitals |
Country | United Kingdom |
Start | 03/2022 |
End | 11/2022 |
Description | Small Molecules TIN Pilot Data Fund |
Amount | £10,000 (GBP) |
Organisation | University College London |
Sector | Academic/University |
Country | United Kingdom |
Start | 03/2022 |
End | 09/2022 |
Description | UCL Therapeutic Acceleration Support |
Amount | £80,000 (GBP) |
Funding ID | 185683 |
Organisation | LifeArc |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 05/2023 |
End | 06/2024 |
Description | Understanding the role of vitamin B6 dyshomeostasis in epilepsy disorders |
Amount | £200,000 (GBP) |
Funding ID | GN2964 |
Organisation | Action Medical Research |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 06/2023 |
End | 12/2025 |
Title | Transcriptomics on slc39a14 mutants treated with MnCl2 |
Description | Processed counts for the DeTCT data presented in Tuschl et al. 2020 (doi: https://doi.org/10.1101/2020.01.31.921130) slc39a14-mn-grcz11-samples.txt contains the sample information (SampleID, Genotype, Treatment etc) slc39a14-mn-grcz11.tsv contains the count information for the measured regions with associated gene information. |
Type Of Material | Database/Collection of data |
Year Produced | 2022 |
Provided To Others? | Yes |
Impact | available to research community |
URL | https://figshare.com/articles/dataset/Transcriptomics_on_slc39a14_mutants_treated_with_MnCl2/1180878... |
Description | Exploiting membrane transporters to target manganese neurotoxicity - Giulio Superti-Furga |
Organisation | CeMM Research Center for Molecular Medicine |
Country | Austria |
Sector | Academic/University |
PI Contribution | Together with Prof Superti-Furga we will jointly supervise a postdoc as part of the CeMM Pre-ERC Postdoc Program. The postdoc is funded through MUW. |
Collaborator Contribution | Provide funding and sponsorship for the postdoc |
Impact | only starting now |
Start Year | 2024 |
Description | Exploiting membrane transporters to target manganese neurotoxicity - Giulio Superti-Furga |
Organisation | Medical University of Vienna |
Country | Austria |
Sector | Academic/University |
PI Contribution | Together with Prof Superti-Furga we will jointly supervise a postdoc as part of the CeMM Pre-ERC Postdoc Program. The postdoc is funded through MUW. |
Collaborator Contribution | Provide funding and sponsorship for the postdoc |
Impact | only starting now |
Start Year | 2024 |
Description | Manganese chelator development - John Spencer/George Kostakis |
Organisation | University of Sussex |
Department | Department of Chemistry |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Providing an animal disease model for drug screening |
Collaborator Contribution | Development and identification of manganese chelators |
Impact | N/A - Work still ongoing |
Start Year | 2014 |
Description | Metal mapping in zebrafish - London Metallomics Facility |
Organisation | King's College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Providing zebrafish sections of Mn transporter mutants for analysis |
Collaborator Contribution | London Metallomics Facility performs LA-ICP-MS analysis of zebrafish brain sections |
Impact | Preliminary results to generate brain Mn map |
Start Year | 2019 |
Description | Mn measurements - Ramon Gonzalez-Mendez |
Organisation | University of Sussex |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Allowed joint publication. |
Collaborator Contribution | Processing of samples for Mn estimation. |
Impact | Publication currently under review by Nature Communications |
Start Year | 2013 |
Description | MnLamP sensor - Joseph Cotruvo |
Organisation | Penn State University |
Department | Penn State Abington |
Country | United States |
Sector | Academic/University |
PI Contribution | N/A |
Collaborator Contribution | Shared plasmid for manganese sensor |
Impact | no outputs yet |
Start Year | 2023 |
Description | Mouse work - Slc30A10-/- (Ahad Rahim) |
Organisation | University College London |
Department | School of Pharmacy |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | provision of mouse model |
Collaborator Contribution | sharing of expertise and equipment |
Impact | Establishing disease model for drug testing |
Start Year | 2021 |
Description | Preformulation studies - Catherine Tuleau (UCL SoP) |
Organisation | University College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | drug screening in zebrafish |
Collaborator Contribution | preformulation studies to be pursued |
Impact | collaboration only just established. multidisciplinary - neuroscience & paediatric pharmaceutics |
Start Year | 2022 |
Description | Sanger Transcript Counting - Elisabeth Busch |
Organisation | The Wellcome Trust Sanger Institute |
Country | United Kingdom |
Sector | Charity/Non Profit |
PI Contribution | Joint publication |
Collaborator Contribution | Analysis of samples (RNA sequencing) |
Impact | Joint publication planned |
Start Year | 2014 |
Description | Slc30a10 knockout mouse and Hep3B cell line - Tom Bartnikas |
Organisation | Brown University |
Country | United States |
Sector | Academic/University |
PI Contribution | Characterisation of disease models |
Collaborator Contribution | Material - Slc30a10 knockout mouse and cell line |
Impact | only recently established |
Start Year | 2020 |
Description | Slc30a10/Slc39a14 LOF zebrafish - Andrew Grierson |
Organisation | University of Sheffield |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Shared zebrafish lines |
Collaborator Contribution | N/A |
Impact | only just started |
Start Year | 2024 |
Description | Slc39a14 KO mouse - Tolunay Aydemir |
Organisation | Cornell University |
Country | United States |
Sector | Academic/University |
PI Contribution | - We will perform LA-ICP-MS on mouse brain samples - We will perform IHC studies on human brain samples |
Collaborator Contribution | - The Aydemir group will share the Slc39a14 KO model |
Impact | only just started |
Start Year | 2024 |
Description | Zf eye collaboration - Stefan Neuhauss |
Organisation | University of Zurich |
Department | Neurosciences |
Country | Switzerland |
Sector | Academic/University |
PI Contribution | Provided animal model |
Collaborator Contribution | Functional characterisation of animal model |
Impact | providing results for publication |
Start Year | 2016 |
Description | Action Medical Research - Staff Meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Third sector organisations |
Results and Impact | Presented research outcomes to Action Medical Research ~80 charity members present. |
Year(s) Of Engagement Activity | 2023 |
Description | YPAG (Young person's advisory group) meeting Great Ormond Street Hospital |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | 30 young people attended online meeting to inform about current research. Help with improving lay abstracts. |
Year(s) Of Engagement Activity | 2022 |