Exosomal protein deficiencies: how abnormal RNA metabolism results in childhood-onset neurological diseases
Lead Research Organisation:
University of Cambridge
Department Name: Clinical Neurosciences
Abstract
All genes are copied into short-lived RNA molecules, which are then translated to protein, forming the building box of the cells in the body. The transcription of DNA, the processing of pre-mRNA into mature mRNA (splicing), the degradation of mRNA and the translation into proteins are all tightly regulated. Both too much and too little of a certain RNA species could be dangerous for a cell, but our understanding of the mechanisms to fine-tune the RNA amounts is still limited. The regulation of gene expression (RNA metabolism) is of utmost importance for normal cell function, nerve cells, however, seem less able to cope with errors. This is illustrated by an increasing number of severe inherited neurological diseases of infancy or childhood caused by a defect in the RNA production machinery; these disorders are characterized by abnormalities of the development and/or the structure of the brain and the central nervous system.
The aim of this proposal is to study and characterize a novel form of RNA related neurological disorder due to dysfunction of a multi-protein complex called the human exosome. The role of the exosome consists of degradation and maturation of RNA. Mutations in the exosome subunit gene EXOSC3 were reported in patients with infantile-onset degeneration of the brainstem and cerebellum and muscle weakness due to spinal motor neuron dysfunction. We have recently identified mutations in EXOSC8, encoding another component of the human exosome, in infants with a similar severe neurological disease. In addition, these children also lose myelin in the brain and spinal cord, which normally coats and insulates nerves and serves to speed up signalling. We also identified a homozygous mutation in a novel gene RBM7 in a child with severe spinal motor neuron dysfunction. RBM7 is an interacting partner of the human exosome. The severe and isolated neurological symptoms in these children raise the possibility that the exosome is particularly important in neurons; however, there are still many open questions.
The aim of this proposal is to further characterize the role of the exosome in nerve cells and will address the following aspects:
1. Neuronal cells from patients: We will analyse RNA levels in patient derived skin cells and will transform them into neuronal cells with recently published methods. We will determine which RNA species are modified by changes in the exosome in the different cell types.
2. Genetically modified zebrafish: In parallel, we will create zebrafish models of exosomal protein deficiencies. By artificially removing single exosome components and by introducing mutations in zebrafish embryos we will explore its effect on the development and function of the brain and different types of neurons. In addition, we will also study the effect of modifying the exosome on myelin formation in zebrafish.
Our results will identify the most important roles of the exosome in regulating gene expression and why is it more damaging for neurons. Combining the data in human cells and zebrafish will enable us to better define the important genes and interacting partners of the exosome. By modifying exosome components or some of the here identified interacting factors we may discover potential pathways to alter RNA degradation or processing in neurons, which can be further developed as a therapeutic approach in exosomal diseases or in other types of neurodegenerative diseases caused by abnormal RNA function.
The aim of this proposal is to study and characterize a novel form of RNA related neurological disorder due to dysfunction of a multi-protein complex called the human exosome. The role of the exosome consists of degradation and maturation of RNA. Mutations in the exosome subunit gene EXOSC3 were reported in patients with infantile-onset degeneration of the brainstem and cerebellum and muscle weakness due to spinal motor neuron dysfunction. We have recently identified mutations in EXOSC8, encoding another component of the human exosome, in infants with a similar severe neurological disease. In addition, these children also lose myelin in the brain and spinal cord, which normally coats and insulates nerves and serves to speed up signalling. We also identified a homozygous mutation in a novel gene RBM7 in a child with severe spinal motor neuron dysfunction. RBM7 is an interacting partner of the human exosome. The severe and isolated neurological symptoms in these children raise the possibility that the exosome is particularly important in neurons; however, there are still many open questions.
The aim of this proposal is to further characterize the role of the exosome in nerve cells and will address the following aspects:
1. Neuronal cells from patients: We will analyse RNA levels in patient derived skin cells and will transform them into neuronal cells with recently published methods. We will determine which RNA species are modified by changes in the exosome in the different cell types.
2. Genetically modified zebrafish: In parallel, we will create zebrafish models of exosomal protein deficiencies. By artificially removing single exosome components and by introducing mutations in zebrafish embryos we will explore its effect on the development and function of the brain and different types of neurons. In addition, we will also study the effect of modifying the exosome on myelin formation in zebrafish.
Our results will identify the most important roles of the exosome in regulating gene expression and why is it more damaging for neurons. Combining the data in human cells and zebrafish will enable us to better define the important genes and interacting partners of the exosome. By modifying exosome components or some of the here identified interacting factors we may discover potential pathways to alter RNA degradation or processing in neurons, which can be further developed as a therapeutic approach in exosomal diseases or in other types of neurodegenerative diseases caused by abnormal RNA function.
Technical Summary
The degradation of mRNAs is an important regulatory step which controls gene expression. Three major degradation systems are responsible for the destruction of transcripts: the 5'-3' exoribonucleases, the nonsense-mediated mRNA decay machinery and the exosome. The exosome degrades and processes a variety of RNA species in the nucleus and in the cytoplasm of eukaryotic cells. The versatility and specificity of the exosome and its associated complexes regulate and maintain the fidelity of gene expression.
A novel group of RNA-associated neurological disorders has been identified with mutations in genes encoding components of the human exosome. Mutations in EXOSC3 were reported in pontocerebellar hypoplasia and spinal motor neuron abnormalities (PCH1). Our group identified EXOSC8 mutations in hypomyelination, spinal muscular atrophy and cerebellar hypoplasia. We showed that the hypomyelination is caused by imbalanced supply of myelin proteins due to disturbed degradation of AU-rich element containing mRNA.
The prominent neurological presentation in these cases raises the possibility that the exosome is particularly important in developing neurons. However, there are many open questions, which will be the focus of this project.
We will investigate which RNA types are affected in their expression or degradation by mutations in the exosome and whether this depends on the cell type and on which exosomal subunit is mutated. We will study human fibroblasts and neuronal cells, converted and differentiated from fibroblasts by recently published methods. Zebrafish will be used as in vivo animal model to analyse how alterations of the exosome affect the development of the nervous system and the myelination of neurons. By combining our results we will identify and further explore novel targets involved in neurodegenerative diseases affecting spinal motor neurons, cerebellar Purkinje cells and oligodendroglia.
A novel group of RNA-associated neurological disorders has been identified with mutations in genes encoding components of the human exosome. Mutations in EXOSC3 were reported in pontocerebellar hypoplasia and spinal motor neuron abnormalities (PCH1). Our group identified EXOSC8 mutations in hypomyelination, spinal muscular atrophy and cerebellar hypoplasia. We showed that the hypomyelination is caused by imbalanced supply of myelin proteins due to disturbed degradation of AU-rich element containing mRNA.
The prominent neurological presentation in these cases raises the possibility that the exosome is particularly important in developing neurons. However, there are many open questions, which will be the focus of this project.
We will investigate which RNA types are affected in their expression or degradation by mutations in the exosome and whether this depends on the cell type and on which exosomal subunit is mutated. We will study human fibroblasts and neuronal cells, converted and differentiated from fibroblasts by recently published methods. Zebrafish will be used as in vivo animal model to analyse how alterations of the exosome affect the development of the nervous system and the myelination of neurons. By combining our results we will identify and further explore novel targets involved in neurodegenerative diseases affecting spinal motor neurons, cerebellar Purkinje cells and oligodendroglia.
Planned Impact
Despite major advances in diagnosing inherited neurological diseases, our understanding of neuronal death pathways in the majority of disorders is still limited and there are very few effective therapies. The importance of RNA processing in neurodegeneration is highlighted with a rapidly increasing number of inherited human neurological diseases caused by mutations in proteins involved in mRNA metabolism including spinal muscular atrophy (SMA) and pontocerebellar hypoplasias (PCH).
A novel mechanism of RNA-associated neurodegeneration has been suggested by the identification of mutations in genes encoding human exosome components. Mutations in EXOSC3 were reported in pontocerebellar hypoplasia and spinal motor neuron abnormalities (PCH1), and our group recently identified mutations in a novel gene EXOSC8, encoding a core component of the human exosome in children with overlapping symptoms of cerebellar hypoplasia, spinal muscular atrophy and hypomyelination. We also detected mutations in another exosome related gene RBM7 in a child with the clinical presentation of spinal muscular atrophy.
We will investigate in this project how abnormal RNA metabolism due to defect of exosomal proteins (EXOSC8, EXOSC3, RBM7) affect different human cells (fibroblasts, induced neuronal cells, neurons) in vitro. We will explore gene expression (RNASeq) and RNA-protein interactions (CLIP) within the exosome. In parallel we will study different zebrafish models and will investigate whether the primary effect of exosome dysfunction alters neurodevelopment, or triggers neurodegeneration and which structures are most affected by deficient function of components of the exosome. Integration of the data in human cells and zebrafish will facilitate the recognition of important genes and proteins which lead to neuronal dysfunction. Modifications of the exosome and its interacting partners will be further studied with the aim to develop novel, RNA-based therapies for neurodegenerative conditions, such as SMA, pontocerebellar hypoplasias or demyelination, which represent a major cause of infantile mortality.
Expected main benefits
1. Our research will help to diagnose patients with exosomal protein deficiencies. Obtaining the genetic cause enables genetic counselling and prenatal or pre-implantation diagnostic testing.
2. Understanding the disease pathomechanism will provide important information on the role of RNA metabolism in neurons.
3. Our results may be applied to develop novel therapies in exosomal diseases but also potentially in other neurological conditions.
4. Patient organisations, national and international patient registries can be formed as a further benefit of our results.
5. For the broader UK economy appropriate diagnosis, prevention and therapy for disabling and life-threatening disorders will reduce the clinical burden of these disorders.
6. This research fits with the aims of Rare Disorders research, which has become increasingly important and receives priority for national, European and international organisations and funding bodies (NIHR, RD-CONNECT, IRDIRC).
Impact in research
1. Better characterization of developmental and degenerative aspects of exosomal protein deficiencies.
2. Defining whether defective RNA degradation or other effect of the exosome on regulating gene expression (splicing, RNA toxicity) is the main disease mechanisms in human exosome disease.
3. Document the potential power of combining RNASeq and CLIP to unveil abnormal RNA metabolism.
4. Evaluate a novel technology to directly transform and (without iPSCs) differentiate neurons from human fibroblasts.
5. Develop transgenic zebrafish lines with CRISPR/Cas9 technology.
6. Integration of human and zebrafish data to explore deficiencies of neuronal development.
7. Exploring whether manipulation of the exosome may be a feasible approach to alter the mechanism of neurodegenerative disease (SMA, PCH).
A novel mechanism of RNA-associated neurodegeneration has been suggested by the identification of mutations in genes encoding human exosome components. Mutations in EXOSC3 were reported in pontocerebellar hypoplasia and spinal motor neuron abnormalities (PCH1), and our group recently identified mutations in a novel gene EXOSC8, encoding a core component of the human exosome in children with overlapping symptoms of cerebellar hypoplasia, spinal muscular atrophy and hypomyelination. We also detected mutations in another exosome related gene RBM7 in a child with the clinical presentation of spinal muscular atrophy.
We will investigate in this project how abnormal RNA metabolism due to defect of exosomal proteins (EXOSC8, EXOSC3, RBM7) affect different human cells (fibroblasts, induced neuronal cells, neurons) in vitro. We will explore gene expression (RNASeq) and RNA-protein interactions (CLIP) within the exosome. In parallel we will study different zebrafish models and will investigate whether the primary effect of exosome dysfunction alters neurodevelopment, or triggers neurodegeneration and which structures are most affected by deficient function of components of the exosome. Integration of the data in human cells and zebrafish will facilitate the recognition of important genes and proteins which lead to neuronal dysfunction. Modifications of the exosome and its interacting partners will be further studied with the aim to develop novel, RNA-based therapies for neurodegenerative conditions, such as SMA, pontocerebellar hypoplasias or demyelination, which represent a major cause of infantile mortality.
Expected main benefits
1. Our research will help to diagnose patients with exosomal protein deficiencies. Obtaining the genetic cause enables genetic counselling and prenatal or pre-implantation diagnostic testing.
2. Understanding the disease pathomechanism will provide important information on the role of RNA metabolism in neurons.
3. Our results may be applied to develop novel therapies in exosomal diseases but also potentially in other neurological conditions.
4. Patient organisations, national and international patient registries can be formed as a further benefit of our results.
5. For the broader UK economy appropriate diagnosis, prevention and therapy for disabling and life-threatening disorders will reduce the clinical burden of these disorders.
6. This research fits with the aims of Rare Disorders research, which has become increasingly important and receives priority for national, European and international organisations and funding bodies (NIHR, RD-CONNECT, IRDIRC).
Impact in research
1. Better characterization of developmental and degenerative aspects of exosomal protein deficiencies.
2. Defining whether defective RNA degradation or other effect of the exosome on regulating gene expression (splicing, RNA toxicity) is the main disease mechanisms in human exosome disease.
3. Document the potential power of combining RNASeq and CLIP to unveil abnormal RNA metabolism.
4. Evaluate a novel technology to directly transform and (without iPSCs) differentiate neurons from human fibroblasts.
5. Develop transgenic zebrafish lines with CRISPR/Cas9 technology.
6. Integration of human and zebrafish data to explore deficiencies of neuronal development.
7. Exploring whether manipulation of the exosome may be a feasible approach to alter the mechanism of neurodegenerative disease (SMA, PCH).
Organisations
- University of Cambridge (Lead Research Organisation)
- Dokuz Eylül University (Collaboration)
- University of Manchester (Collaboration)
- McGill University (Collaboration)
- Hebrew University of Jerusalem (Collaboration)
- Pontifical Catholic University of Chile (Collaboration)
- Columbia University Medical Center (Collaboration)
- University of Miami (Collaboration)
- University of Antwerp (Collaboration)
- Medical Research Council (MRC) (Collaboration)
- UNIVERSITY OF CAMBRIDGE (Collaboration)
- Broad Institute (Collaboration)
Publications
100,000 Genomes Project Pilot Investigators
(2021)
100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report.
100,000 Genomes Project Pilot Investigators
(2021)
100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report.
in The New England journal of medicine
Abicht A
(2018)
Mitochondrial and nuclear disease panel (Mito-aND-Panel): Combined sequencing of mitochondrial and nuclear DNA by a cost-effective and sensitive NGS-based method.
in Molecular genetics & genomic medicine
Atalaia A
(2021)
Correction to: A guide to writing systematic reviews of rare disease treatments to generate FAIRcompliant datasets: building a Treatabolome.
in Orphanet journal of rare diseases
Atalaia A
(2020)
A guide to writing systematic reviews of rare disease treatments to generate FAIR-compliant datasets: building a Treatabolome.
in Orphanet journal of rare diseases
Atalaia A
(2024)
EURO-NMD registry: federated FAIR infrastructure, innovative technologies and concepts of a patient-centred registry for rare neuromuscular disorders.
in Orphanet journal of rare diseases
Balaraju S
(2020)
Congenital myasthenic syndrome with mild intellectual disability caused by a recurrent SLC25A1 variant.
in European journal of human genetics : EJHG
Description | as Chair of the mitochondrial group within the ERN-NMD I participate in endorsing and making guidelines for mitochondrial diseases |
Geographic Reach | Europe |
Policy Influence Type | Influenced training of practitioners or researchers |
Impact | As the Chair of the mitochondrial group within the EURO-NMD reference network I participate in making diagnosis and management of patients with mitochondrial diseases harmonised in Europe |
URL | https://ern-euro-nmd.eu/ |
Description | Horizon 2020 |
Amount | € 15,000,000 (EUR) |
Organisation | European Union |
Sector | Public |
Country | European Union (EU) |
Start | 01/2018 |
End | 12/2023 |
Description | Investigate new treatment options in zebrafish models of mtDNA depletion syndromes |
Amount | £62,432 (GBP) |
Organisation | The Lily Foundation |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 07/2019 |
End | 07/2021 |
Description | Nuclear mechanisms underpinning mitochondrial vulnerability in different cell-types |
Amount | £4,254,246 (GBP) |
Funding ID | 226653/Z/22/Z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2023 |
End | 09/2028 |
Title | BN-PAGE |
Description | functional analysis of human patient cell lines |
Type Of Material | Cell line |
Provided To Others? | No |
Impact | we revealed the pathomechanism of mitochondrial disease in 20 patients |
Title | Identified molecular serum biomarkers in CMT |
Description | We identify proteins in sera of patients and mouse models with Charcot-Marie-Tooth disease (CMT) with characteristics that make them suitable as biomarkers in clinical practice and therapeutic trials. |
Type Of Material | Physiological assessment or outcome measure |
Year Produced | 2022 |
Provided To Others? | Yes |
Impact | Molecular markers scalable for clinical use are critical for the development of effective treatments and the design of clinical trials. We collected serum from mouse models of CMT1A (C61 het), CMT2D (GarsC201R, GarsP278KY), CMT1X (Gjb1-null), CMT2L (Hspb8K141N) and from CMT patients with genotypes including CMT1A (PMP22d), CMT2D (GARS), CMT2N (AARS) and other rare genetic forms of CMT. The severity of neuropathy in the patients was assessed by the CMT Neuropathy Examination Score (CMTES). We performed multitargeted proteomics on both sample sets to identify proteins elevated across multiple mouse models and CMT patients. We detected that GDF15 and NCAM1 are useful biomarkers in CMT and tehy should be further investigated in clinical trials. |
URL | https://pubmed.ncbi.nlm.nih.gov/35148379/ |
Title | TRMU cells |
Description | we have obtained cells (fibrobalsts and myoblasts) from a patient and established a special technique to study 2-thiolation of mt-tRNAs |
Type Of Material | Cell line |
Provided To Others? | No |
Impact | We are currently investigating the possible role of 2-thiolation as a possible disease mechanism in reversible COX deficiency as part of the project |
Title | iPSC neuronal conversion |
Description | We established the conversion of neurons from iPSCs of patients with mitochondrial disease. |
Type Of Material | Cell line |
Year Produced | 2020 |
Provided To Others? | No |
Impact | We are currently working on these cells and we will publish our results. |
Title | induced neuronal progenitor cells |
Description | We can successfully convert human finroblasts into induced neuronal progenitor cells. |
Type Of Material | Model of mechanisms or symptoms - human |
Provided To Others? | No |
Impact | We have already converted 4 patient and 2 contol cell lines into induced neuronal progenitor cells. Currently the analysis of mitochondrial function is in progress in these cells. |
Title | studying the neuromuscular junction |
Description | co-investigator on a multi-user equipment funded by Wellcome to study electrophysiology of the neuromuscular junction |
Type Of Material | Physiological assessment or outcome measure |
Year Produced | 2018 |
Provided To Others? | Yes |
Impact | no impact yet, equipment is currently being set up |
Title | zebrafish |
Description | I used zebrafish to model human disease. |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Provided To Others? | No |
Impact | Published a paper (Boczonadi et al. 2014) |
Title | Treatabolome database |
Description | My group has participated in the "Treatabolome" project, which is part of the EU Solve-RD. We have performed a systematic review and established the database for treatable genes and variants in Leigh Syndrome. |
Type Of Material | Computer model/algorithm |
Year Produced | 2020 |
Provided To Others? | Yes |
Impact | Leigh syndrome (LS) is the most frequent paediatric clinical presentation of mitochondrial disease. The clinical phenotype of LS is highly heterogeneous. Though historically the treatment for LS is largely supportive, new treatments are on the horizon. Due to the rarity of LS, large-scale interventional studies are scarce, limiting dissemination of information of therapeutic options to the wider scientific and clinical community. We conducted a systematic review of pharmacological therapies of LS following the guidelines for FAIR-compliant datasets. We searched for interventional studies within Clincialtrials.gov and European Clinical trials databases. Randomised controlled trials, observational studies, case reports and case series formed part of a wider MEDLINE search. Though interventional randomised controlled trials have begun for LS, the majority of evidence remains in case reports and case series for a number of treatable genes, encoding cofactors or transporter proteins of the mitochondria. Our findings form part of the international expert-led Solve-RD efforts to assist clinicians initiating treatments in patients with treatable variants of LS. |
URL | https://pubmed.ncbi.nlm.nih.gov/34308912/ |
Title | bioinformatic analysis of RNAseq |
Description | performed RNAseq in several human cell and muscle samples and analysed different parameters to gain understanding of the metabolic signature of neurogenetic diseases |
Type Of Material | Data analysis technique |
Year Produced | 2017 |
Provided To Others? | No |
Impact | papers are currently in progress |
Title | proteomic analysis of cells/tissues |
Description | performed proteomic analysis of paatient cells and skeletal muscle samples |
Type Of Material | Data analysis technique |
Year Produced | 2017 |
Provided To Others? | Yes |
Impact | papers in progress |
Description | Consequitur - cohort of patients from Turkey for WES |
Organisation | Dokuz Eylül University |
Country | Turkey |
Sector | Academic/University |
PI Contribution | We collaborate with Dr. Yavuz Oktay and Dr. Semra Hiz on identiying new disease genes in consanguineous Turkish families with various neurogenetic diseases. |
Collaborator Contribution | Collected 400 families and DNA samples, perfomred phenotyping |
Impact | We are currently writing abstracts for conferences from the first results and drafting papers. |
Start Year | 2016 |
Description | Identifying novel disease genes in hereditary motor neuropathies |
Organisation | University of Miami |
Country | United States |
Sector | Academic/University |
PI Contribution | We have identified mutations in a novel disease gene in a family with autosomal dominant hereditary motor neuropathy. |
Collaborator Contribution | The collaborators also had one family with another mutation in the same gene. |
Impact | We have published a paper together in AJHG. |
Start Year | 2014 |
Description | Metablic testing of serum and lymphoblastoid cells of patients with motor neuropathy |
Organisation | University of Antwerp |
Country | Belgium |
Sector | Academic/University |
PI Contribution | We collected serum and blood samples of patients with hereditary motor neuropathies and Prof. Vincent Timmermann`s group converted them to lymphoblastoid cells and conduct metabolomics studies |
Collaborator Contribution | Prof. Timmermann`s group convert the blood cells to lymphoblastoid cells. |
Impact | samples are currently being analysed |
Start Year | 2016 |
Description | Metabolic measurements in mitochondrial carrier protein deficiency |
Organisation | University of Cambridge |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have patient samples for metabolic measurements to Dr. Christian Frezza`s laboratory. |
Collaborator Contribution | We will receive the results soon and will have a joint publication. |
Impact | no output yet |
Start Year | 2013 |
Description | Next Generation Sequencing |
Organisation | Broad Institute |
Country | United States |
Sector | Charity/Non Profit |
PI Contribution | Prof. Daniel McArthur`s group in the Broad Institute agreed to perform WES in >300 Turkish families with neurogenetic disease. |
Collaborator Contribution | Performed WES for free. |
Impact | currently writing up conference abstracts and papers. |
Start Year | 2016 |
Description | Search for modifyers in reversible COX deficiency |
Organisation | Columbia University Medical Center |
Department | Neurological Institute of New York |
Country | United States |
Sector | Academic/University |
PI Contribution | I contribute a large family and performed exome sequencing |
Collaborator Contribution | contributing further families |
Impact | currently being worked up |
Start Year | 2011 |
Description | Studying 2-thiolation of mt-tRNA Glu, Lys, Gln |
Organisation | McGill University |
Department | Department of Molecular Neurogenetics |
Country | Canada |
Sector | Academic/University |
PI Contribution | I have started to collaborate on the function of TRMU |
Collaborator Contribution | common publication |
Impact | There is a Hom Mol Genet paper (Sasarman et al. 2011) already out of this collaboration. |
Start Year | 2011 |
Description | Studying a novel mitochondrial carriers in a patient mitochondrial disease |
Organisation | Medical Research Council (MRC) |
Department | MRC Mitochondrial Biology Unit |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We identified a patient with mutations in a novel mitochondrial carrier protein. |
Collaborator Contribution | Dr. Edmund Kunji`s laboratory performed functional analysis of the carrier to prove that the mutation is pathogenic. |
Impact | We are currently drafting a manuscript. |
Start Year | 2014 |
Description | Studying the function of the exosome in human disease. |
Organisation | Hebrew University of Jerusalem |
Department | Hebrew University Hadassah Medical School |
Country | Israel |
Sector | Academic/University |
PI Contribution | We have identified a novel disease gene and performed functional studies. |
Collaborator Contribution | The partner had another family with mutations in the same gene. |
Impact | We published a nice paper together (Boczonadi et al. 2014) |
Start Year | 2014 |
Description | mitochondrial fusion/fission |
Organisation | Pontifical Catholic University of Chile |
Country | Chile |
Sector | Academic/University |
PI Contribution | I have sent cell lines to Dr. Veronica Eisner for studiying mitochondrial fusion/fission. |
Collaborator Contribution | studying mitochondrial fission in cells with a special technique |
Impact | A novel mechanism causing imbalance of mitochondrial fusion and fission in human myopathies. Bartsakoulia M, Pyle A, Troncosco D, Vial J, Paz-Fiblas MV, Duff J, Griffin H, Boczonadi V, Lochmüller H, Kleinle S, Chinnery PF, Grünert S, Kirschner J, Eisner V, Horvath R. Hum Mol Genet. 2018 Jan 19. doi: 10.1093/hmg/ddy033. [Epub ahead of print] PMID: 29361167 |
Start Year | 2015 |
Description | mitochondrial tRNA synthetase related diseases |
Organisation | University of Manchester |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | I started a collaboration with Prof. William Newman on mt tRNA synthetase diseases. I sent him DNA samples of patients with potential Perrault syndrome. |
Collaborator Contribution | Dr. Newmn is sequencing with a NGS panel novel genes which could cause Perrault syndrorme. |
Impact | no output yet |
Start Year | 2015 |
Description | search for biomarkers in CMT |
Organisation | University of Antwerp |
Country | Belgium |
Sector | Academic/University |
PI Contribution | We have performed targeted proteomics on serum of patients with CMT. We extended the analysis on mouse models of CMT. |
Collaborator Contribution | We have received serum from mouse models of CMT from Prof. Vincent Timmermann`s team. We search for biomarkers in CMT in this collaboration. |
Impact | submitted an abstract to the UK MRC Translational Research Conference (22-23 April, UCL) |
Start Year | 2019 |
Title | A Study of Bezafibrate in Mitochondrial Myopathy" (NUTH NHS Trust, 2015) |
Description | We are testing the feasibility of bezafibrate supplementation in MELAS. Trial has been finished. We published the paper very recently in EMBO Mol Med |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Early clinical assessment |
Year Development Stage Completed | 2019 |
Development Status | Under active development/distribution |
Impact | trial has not shown clinical benefit |
Description | Organizing SHORT VIDEO AND a lightshow for the Mitochondrial Awareness week |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Supporters |
Results and Impact | We organized a lightshow and produced a short video for the Mitochondrial Awareness Week. |
Year(s) Of Engagement Activity | 2020 |
Description | Webinar for MDUK |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | I gave a presentation at a MDUK webinar about the research in my group. |
Year(s) Of Engagement Activity | 2023 |
Description | creating video about patient journey for European Joint Program |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | We actively participated in making a video about a patient journey of a Turkish patient who we dignosed within our research for the European Joint Program activities. |
Year(s) Of Engagement Activity | 2019 |
URL | https://twitter.com/GA4GH/status/1186993739991900165?s=17 |