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Projects / Programmes source: ARIS

Transport and RNA binding of TDP-43 and FUS - implications for ALS/FTLD spectrum of neurodegenerative disease

Research activity

Code Science Field Subfield
3.03.00  Medical sciences  Neurobiology   

Code Science Field
B640  Biomedical sciences  Neurology, neuropsychology, neurophysiology 

Code Science Field
3.05  Medical and Health Sciences  Other medical sciences 
Keywords
neurodegeneration, frontotemporal lobar degeneration, amyoptrophic lateral sclerosis, TDP-43, FUS, RNA
Evaluation (rules)
source: COBISS
Researchers (26)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  28627  PhD Sofija Anđelić  Neurobiology  Researcher  2011 - 2013  76 
2.  23598  PhD Tomaž Bratkovič  Pharmacy  Researcher  2011 - 2014  242 
3.  18548  PhD Helena Haque Chowdhury  Neurobiology  Researcher  2011 - 2014  155 
4.  27585  PhD Jernej Jorgačevski  Medical sciences  Researcher  2011 - 2014  180 
5.  04648  PhD Janko Kos  Biotechnical sciences  Researcher  2011  1,166 
6.  30697  PhD Anja Kovanda  Neurobiology  Researcher  2012 - 2014  77 
7.  29604  PhD Bojana Kranjc Mirković  Pharmacy  Researcher  2011  67 
8.  15666  PhD Marko Kreft  Neurobiology  Researcher  2011 - 2013  685 
9.  25096  PhD Mojca Lunder  Pharmacy  Researcher  2011  260 
10.  23346  PhD Tina Pangršič Vilfan  Neurobiology  Researcher  2011 - 2013  49 
11.  29470  PhD Katarina Pegan  Biochemistry and molecular biology  Researcher  2011 - 2013  44 
12.  26507  PhD Jure Pohleven  Biochemistry and molecular biology  Researcher  2011 - 2013  75 
13.  21390  PhD Maja Potokar  Medical sciences  Researcher  2011 - 2014  161 
14.  32900  PhD Nataša Radić  Medical sciences  Researcher  2012  36 
15.  24291  PhD Katja Rebolj  Neurobiology  Researcher  2013  57 
16.  22459  PhD Tadeja Režen  Neurobiology  Researcher  2011 - 2012  246 
17.  32000  PhD Boštjan Rituper  Microbiology and immunology  Researcher  2014  68 
18.  15813  PhD Boris Rogelj  Neurobiology  Head  2011 - 2014  412 
19.  07849  PhD Borut Štrukelj  Biochemistry and molecular biology  Researcher  2011 - 2013  1,129 
20.  31572  PhD Saša Trkov Bobnar  Microbiology and immunology  Researcher  2011 - 2014  56 
21.  20214  PhD Nina Vardjan  Neurobiology  Researcher  2011 - 2014  269 
22.  35506  PhD Sabina Vatovec  Biology  Researcher  2013 - 2014  29 
23.  32525  PhD Jelena Velebit Marković  Neurobiology  Researcher  2011 - 2013  40 
24.  32038  PhD Miha Vodnik  Pharmacy  Researcher  2013  24 
25.  17285  Darja Žunič Kotar    Technical associate  2011 - 2014 
26.  15640  PhD Vera Župunski  Biochemistry and molecular biology  Researcher  2011 - 2014  190 
Organisations (5)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0103  University of Ljubljana, Faculty of Chemistry and Chemical Technology  Ljubljana  1626990  23,454 
2.  0106  Jožef Stefan Institute  Ljubljana  5051606000  91,961 
3.  0381  University of Ljubljana, Faculty of Medicine  Ljubljana  1627066  48,743 
4.  0787  University of Ljubljana, Faculty of Pharmacy  Ljubljana  1626973  17,415 
5.  1683  Celica BIOMEDICAL  Ljubljana  1506854  1,802 
Abstract
Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are two ends of a phenotypic spectrum of disabling, relentlessly progressive and ultimately fatal diseases. There is no treatment and until recently we have known very little about their causes. Recent genetic and pathological discoveries have placed TDP-43 (TAR DNA binding protein) and FUS (fused in sarcoma) proteins at centre stage in the pathogenesis of ALS and FTLD. Cytoplasmic TDP-43 positive inclusions have also been described in a 30% of Alzheimer cases, 20% of Dementia with Lewy bodies and a variety of other neurodegenerative conditions. Both TDP-43 and FUS have some striking similarities: a) mutations in both genes that have been linked to ALS cluster in the C terminal of both proteins; b) both are predominantly nuclear proteins but accumulate in the cytoplasm in disease forming large inclusions; c) they both have DNA and RNA binding domains and are known to take part in RNA processing and regulation. Aberrant processing and sequestration of these two proteins may directly contribute to neurodegeneration through a loss of function (e.g. loss of RNA processing in the nucleus), however, they both also form aggregates in affected neurons and therefore may also act through a toxic gain of function. These functional similarities between TDP-43 and FUS point to a crucial pathogenic pathway potentially involving RNA processing and transport. Before the recent discovery of their involvement in ALS and FTLD, there have not been many reports concerning the function of both proteins (more so for FUS, which is involved in some sarcomas). Therefore, additional functional characterization of both proteins is warranted in order to gain more insight into the mechanisms of disease progression. One of the principal aims of this project is to combine and correlate the data obtained from proteomic, transcriptomic and RNA target research from TDP-43 and FUS, to obtain a global overview of the effects of the gain or loss of function of these two proteins. Whether the disease process occurs via the loss of function or gain of function and the disease relevance of principal target proteins will be analysed in TDP-43 or FUS mutation-containing, patient derived, induced pluripotent stem cells, transgenic mouse models and post-mortem human disease brain and spinal cord tissues. Further, we want to characterise the mechanisms of intra- and intercellular transport of TDP-43 and FUS as well as develop ligands that will influence their protein-protein and protein-RNA interactions. Additionally, we aim to screen rodent models of different neurological disorders for aberrant TDP-43 or FUS expression as these may help with the triangulation of systemic in vivo processes and changes required for the disease onset and progression.
Significance for science
ALS and FTLD are terminal neurological disorders for which there is no known cure. Recent findings strongly implicate disturbances in RNA processes in this spectrum disorder. Numerous other high-impact publications suggest the arising importance of RNA-related processes in understanding complex diseases and in the development of novel therapies. The main aim of this project was to investigate the disease relevant functional changes of TDP-43 and FUS. As they are both RNA binding proteins the pathological changes in RNA metabolism is also implicated. During the duration of the project we have published eight original research papers and two reviews. All together they have 331 citations (Source WoS) to date.
Significance for the country
The funding of the proposed project has enabled continuation of expansion of research in molecular neurodegeneration in Slovenia. Additionally, it has insured continuation of very fruitful collaboration between the applicant institutions in Slovenia with the Centre for Neurodegeneration Research from King's College London, UK, and with MRC laboratory for molecular biology in Cambridge UK. The proposed project has also enabled increased incorporation of Slovenian scientists into European and world initiatives, such as recently set up ENCALS (European Network for the Cure of ALS). Young postdoctoral scientists and up one PhD students have also contributed to the project, broadening their knowledge and providing opportunities to be involved in cutting-edge, world-class, and high-impact research. The PhD student also spent eight months in KCL through a stipend by Ad Futura. As an expert in molecular basis of ALS, the head of the project was honored with public lecture for ALS patients and carers on the international ALS day and the 10th aniversary of the ALS group within the Slovenian muscular dystrophy society.
Most important scientific results Annual report 2011, 2012, 2013, final report, complete report on dLib.si
Most important socioeconomically and culturally relevant results Annual report 2011, 2012, 2013, final report, complete report on dLib.si
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