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Projects / Programmes source: ARIS

Pathogenic role of paraspeckle-like nuclear bodies in neurodegenerative diseases ALS and FTD

Research activity

Code Science Field Subfield
3.03.00  Medical sciences  Neurobiology   

Code Science Field
B640  Biomedical sciences  Neurology, neuropsychology, neurophysiology 

Code Science Field
3.01  Medical and Health Sciences  Basic medicine 
Keywords
amyotrophic lateral sclerosis, frontotemporal dementia, neurodegeneration, RNA-binding proteins, RNA toxicity, paraspeckles, C9ORF72
Evaluation (rules)
source: COBISS
Researchers (13)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  24866  Samo Belavič Pučnik  Public health (occupational safety)  Researcher  2018 - 2021  88 
2.  37546  PhD Janja Božič  Medical sciences  Researcher  2019 - 2021  30 
3.  23399  PhD Tomaž Curk  Computer science and informatics  Researcher  2018 - 2021  254 
4.  35424  PhD Tomaž Hočevar  Computer science and informatics  Researcher  2020 - 2021  30 
5.  29860  PhD Voyko Kavcic  Neurobiology  Researcher  2018 - 2020  159 
6.  16345  PhD Tomaž Marš  Neurobiology  Researcher  2018 - 2021  345 
7.  50784  PhD Miha Modic  Biochemistry and molecular biology  Researcher  2018 - 2020  59 
8.  21397  PhD Helena Motaln  Biochemistry and molecular biology  Researcher  2018 - 2021  208 
9.  33169  PhD Eva Ogorevc  Biotechnology  Researcher  2020 - 2021  38 
10.  28351  PhD Sergej Pirkmajer  Neurobiology  Researcher  2018 - 2021  466 
11.  24291  PhD Katja Rebolj  Neurobiology  Researcher  2019  57 
12.  15813  PhD Boris Rogelj  Neurobiology  Head  2018 - 2021  412 
13.  15600  MSc Maja Šimaga    Technical associate  2018 - 2021 
Organisations (3)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0106  Jožef Stefan Institute  Ljubljana  5051606000  91,921 
2.  0381  University of Ljubljana, Faculty of Medicine  Ljubljana  1627066  48,724 
3.  1539  University of Ljubljana, Faculty of Computer and Information Science  Ljubljana  1627023  16,690 
Abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two phenotypic manifestations of a devastating neurodegenerative disease. Cytoplasmic mislocalization and aggregation of otherwise nuclear RNA binding proteins are the hallmark pathological features of both, ALS and FTD. In 95% of all ALS and 60% of FTD patients the aggregating protein is TDP-43, thus defining those cases as TDP-43 proteinopathies. However, only a very small percentage of aggregation is actually caused by mutations within TDP-43. To understand the disease processes and find novel treatment approaches, discerning signaling pathways causative for aggregation of wildtype TDP-43 became the main focus of the ALS and FTD research fields. Changes in TDP43 localization were shown to arise also from disease-causing mutations in other genes, the most common being TDP-43 proteinopathy-associated GGGGCC ((G4C2)n) hexanucleotide repeat expansion (HRE) mutation in C9ORF72 gene.   The exact mechanism linking HRE mutation to TDP-43 aggregation is still unclear. The mutation is proposed to cause toxicity and neurodegeneration via three pathogenic mechanisms: haploinsufficiency, (G4C2)n RNA toxicity and toxicity of translated dipeptide repeats. With the focus on RNA toxicity, we and others have reported on a number of RNA binding proteins (RBPs) that bind (G4C2)n RNA in vitro, colocalize with (G4C2)n nuclear aggregates called RNA foci, and form ribonucleoprotein (RNP) complexes in transfected cells and in mutant C9ORF72 post-mortem brains. Among the reported proteins, there were hnRNPH, SFPQ and NONO, which are the essential components of nuclear RNPs called paraspeckles. The role of paraspeckles is suggested to be a sequestration of RBPs and RNAs, and it is the resemblance of (G4C2)n RNA foci to paraspeckles that represents the key starting point of this proposal.   The aim of the proposed project is the characterization of structure and function of (G4C2)n RNA foci in the context of their role in pathogenesis of ALS and FTD, converging on regulation of their formation as an approach to therapy. The main objectives are:   1) Creation of (G4C2)n RNA - human embryonic stem cells model. 2) Identification of RBPs regulated by (G4C2)n RNA in hESC. 3) Detailed characterization of RNA foci in comparison with paraspeckles. 4) Assessment of RNA foci pathological significance in Drosophila model and post-mortem brain tissue. 5) Defining therapeutic potential of regulating RNA-foci formation.   We propose to achieve our goals by implementing the newest cutting-edge procedures, such as RBPomics, transcript specific RBDmapping, and advanced bioinformatics that are all available to collaborating groups. These will, in combination with validation in newly established disease models and patient tissues, provide a profound insight into crucial neurodegeneration-related molecular processes and facilitate the search for cures. By unraveling structural and functional characteristics of (G4C2)n RNA foci, the proposed project will lead into a new research direction development, displaying essential for understanding regulation and pathogenesis of C9ORF72-associated diseases, as well as understanding the basic role of RNP in the nucleus.   The excellence of PI and international collaborators, with extensive experience in determining RNA-protein interactions, large data handling and molecular mechanisms and modelling of ALS and FTD, makes us very well positioned to carry out and succeed in research presented in this proposal.
Significance for science
ALS and FTD are fatal neurological disorders for which there is no existing cure. Recent findings strongly implicate disturbances in RNA processes in these disorders. Studies from numerous high-impact publications demonstrate the role that perturbations in RNA-related processes have in those diseases and claim that unravelling their regulation would widen understanding of other complex diseases and accelerate development of novel therapies. The main goal of the proposed project is to reveal the regulation of RNA foci (RNA-protein structures) formation and how this signifies in disease development. RNA foci form on scaffold of (G4C2)n RNA transcribed from the hexanucleotide repeat expansion (HRE), a mutation within the C9ORF72 gene, which is the most common genetic cause of ALS and FTD. Funding the proposed project will enable continuation of cutting-edge research in molecular neurodegeneration in Slovenia and will ensure continuation of a very fruitful collaboration with prof. Shaw and prof. Hirth from King's College London, UK, as well as with dr. Castello from the renowned Department of Biochemistry, University of Oxford, UK. Young scientists and PhD students will also benefit from the project. Their active involvement in the project research will broaden their knowledge and provide them opportunities to develop networks and gain experience, while participating in this high-impact research. With this in mind, we also plan PhD student visits to the laboratories of our foreign collaborators covered by the ERASMUS+ grants. The proposed project will also increase visibility and enrolment of Slovenian scientists in European and world initiatives, such as ENCALS (European Network for the Cure of ALS) or Project MinE (ALS genetic research). The success of our ALS research and clinical practice in Slovenia has already contributed to the decision of ENCALS to host its 2017 meeting in Ljubljana. A recent report in UK has shown that in 2015 dementia has become the leading cause of death. There are no drugs that could improve the course of any neurodegenerative disorder, slow or prevent disease progression. Our understanding of the molecular basis of these diseases thus urgently needs to be improved to identify novel drug targets and develop more effective interventions. With this in mind, countries like USA and UK are already increased their investment into neurodegeneration research. UK’s first Dementia Research Institute was built in 2017 and will receive up to L150 million to drive forward research and innovation in fighting dementia. The results of our research will be disseminated at international conferences and workshops and by publishing in leading research journals. As high ranking member of the Slovenian Neuroscience Society, Dr. Rogelj will continue to be involved in neuroscience promotion to raise awareness of the neuroscience in general and the importance of understanding and finding cures for neurodegenerative diseases and other brain disorders.
Significance for the country
ALS and FTD are fatal neurological disorders for which there is no existing cure. Recent findings strongly implicate disturbances in RNA processes in these disorders. Studies from numerous high-impact publications demonstrate the role that perturbations in RNA-related processes have in those diseases and claim that unravelling their regulation would widen understanding of other complex diseases and accelerate development of novel therapies. The main goal of the proposed project is to reveal the regulation of RNA foci (RNA-protein structures) formation and how this signifies in disease development. RNA foci form on scaffold of (G4C2)n RNA transcribed from the hexanucleotide repeat expansion (HRE), a mutation within the C9ORF72 gene, which is the most common genetic cause of ALS and FTD. Funding the proposed project will enable continuation of cutting-edge research in molecular neurodegeneration in Slovenia and will ensure continuation of a very fruitful collaboration with prof. Shaw and prof. Hirth from King's College London, UK, as well as with dr. Castello from the renowned Department of Biochemistry, University of Oxford, UK. Young scientists and PhD students will also benefit from the project. Their active involvement in the project research will broaden their knowledge and provide them opportunities to develop networks and gain experience, while participating in this high-impact research. With this in mind, we also plan PhD student visits to the laboratories of our foreign collaborators covered by the ERASMUS+ grants. The proposed project will also increase visibility and enrolment of Slovenian scientists in European and world initiatives, such as ENCALS (European Network for the Cure of ALS) or Project MinE (ALS genetic research). The success of our ALS research and clinical practice in Slovenia has already contributed to the decision of ENCALS to host its 2017 meeting in Ljubljana. A recent report in UK has shown that in 2015 dementia has become the leading cause of death. There are no drugs that could improve the course of any neurodegenerative disorder, slow or prevent disease progression. Our understanding of the molecular basis of these diseases thus urgently needs to be improved to identify novel drug targets and develop more effective interventions. With this in mind, countries like USA and UK are already increased their investment into neurodegeneration research. UK’s first Dementia Research Institute was built in 2017 and will receive up to L150 million to drive forward research and innovation in fighting dementia. The results of our research will be disseminated at international conferences and workshops and by publishing in leading research journals. As high ranking member of the Slovenian Neuroscience Society, Dr. Rogelj will continue to be involved in neuroscience promotion to raise awareness of the neuroscience in general and the importance of understanding and finding cures for neurodegenerative diseases and other brain disorders.
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