Projects / Programmes source: ARIS

Dysregulation of TDP-43 expression in amyotrophic lateral sclerosis and frontotemporal lobar degeneration

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 
Frontotemporal dementia, amiotrofic lateral sclerosis, TDP-43, C9orf72, RNA, neurodegeneration
Evaluation (rules)
source: COBISS
Researchers (25)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  23598  PhD Tomaž Bratkovič  Pharmacy  Researcher  2013 - 2016  233 
2.  35462  PhD Simona Darovic  Biochemistry and molecular biology  Junior researcher  2013 - 2016  36 
3.  15400  PhD Leja Dolenc Grošelj  Neurobiology  Researcher  2013 - 2016  518 
4.  04410  PhD Zoran Grubič  Neurobiology  Researcher  2013 - 2016  384 
5.  21239  PhD Blaž Koritnik  Medical sciences  Researcher  2013 - 2016  274 
6.  04648  PhD Janko Kos  Biotechnical sciences  Researcher  2013 - 2016  1,154 
7.  30697  PhD Anja Kovanda  Neurobiology  Researcher  2013 - 2014  73 
8.  34385  PhD Jasna Lojk  Metabolic and hormonal disorders  Researcher  2015  68 
9.  25096  PhD Mojca Lunder  Pharmacy  Researcher  2013 - 2016  254 
10.  16345  PhD Tomaž Marš  Neurobiology  Researcher  2013 - 2016  344 
11.  19318  PhD Katarina Miš  Neurobiology  Researcher  2013 - 2016  191 
12.  28351  PhD Sergej Pirkmajer  Neurobiology  Researcher  2013 - 2016  448 
13.  26507  PhD Jure Pohleven  Biochemistry and molecular biology  Researcher  2013  74 
14.  30710  PhD Sonja Prpar Mihevc  Neurobiology  Researcher  2015 - 2016  108 
15.  30887  PhD Anja Pucer Janež  Pharmacy  Researcher  2014 - 2015  58 
16.  34292  Gregor Ramovš    Technical associate  2013 - 2014 
17.  29603  PhD Matjaž Ravnikar  Pharmacy  Researcher  2013 - 2016  70 
18.  24291  PhD Katja Rebolj  Neurobiology  Researcher  2013 - 2014  57 
19.  15813  PhD Boris Rogelj  Neurobiology  Head  2013 - 2016  410 
20.  32524  Jana Stanič    Technical associate  2016  13 
21.  33328  PhD Maja Štalekar  Biochemistry and molecular biology  Researcher  2013 - 2016  49 
22.  07849  PhD Borut Štrukelj  Biochemistry and molecular biology  Researcher  2013 - 2016  1,120 
23.  08780  PhD Janez Zidar  Neurobiology  Researcher  2013 - 2016  407 
24.  17285  Darja Žunič Kotar    Technical associate  2013 - 2016 
25.  15640  PhD Vera Župunski  Biochemistry and molecular biology  Researcher  2013 - 2016  185 
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  23,314 
2.  0106  Jožef Stefan Institute  Ljubljana  5051606000  89,894 
3.  0312  University Medical Centre Ljubljana  Ljubljana  5057272000  76,230 
4.  0381  University of Ljubljana, Faculty of Medicine  Ljubljana  1627066  46,255 
5.  0787  University of Ljubljana, Faculty of Pharmacy  Ljubljana  1626973  17,515 
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two ends of a phenotypic spectrum of disabling, relentlessly progressive and ultimately fatal diseases. There is no cure and until recently we have known very little about their causes. Cytoplasmic TDP-43 positive inclusions are a hallmark of the disease spectrum and can be found in 95% of all ALS and 50% of FTLD cases, which can now be aptly termed TDP-43 proteinopathies. In order to understand the disease process and look for ways of treatment, discerning pathways that may bring about TDP-43 aggregation is one of the main focuses in the field of ALS and FTLD research. Current understanding is that changes in de novo synthesis levels, localisation and turnover of TDP-43 may all have a role to play in ALS/FTLD. Cellular and animal model studies have shown that just overexpression of TDP-43 can be pathogenic. We aim to study regulation of TDP-43 expression at the RNA level and involvement of these processes in TDP-43 proteinopathies. The disease importance of RNA related upstream processes has just been further substantiated with association of the GGGGCC expanded repeat in C9orf72 with ALS/FTLD. Using an RNA pull-down method we have shown that TDP-43 3’UTR binds TDP-43 and FUS proteins. In this project we propose to use proteomic approaches to discover other RNA binding proteins (RBPs) that may bind to and regulate TDP-43 mRNA. Using the same method we propose to discover proteins that bind to GGGGCC repeat. We also aim to use phage display of scFvs (single-chain variable fragments of antibodies) to develop a tool for diagnostic analysis of GGGGCC repeats. Cellular stress is another important factor associated with ALS and FTLD. Oxidative stress has been shown to affect transcriptional and translational fidelity leading to increased misincorporation of amino acids. Our preliminary data shows that oxidative stress can affect the isoelectric point of TDP-43 suggestive of amino acid misincorporation. We propose to define the extent and types of misincorporation in TDP-43. The disease relevance of these findings will be tested on TDP-43 transgenic mouse models, inducible pluripotent stem cells containing TDP-43 mutations and postmortem CNS brain and spinal cord tissue from ALS and FTLD patients with TDP-43 proteinopathy. The objectives of the project are following: - Discovery of RBPs that bind to TDP-43 mRNA and GGGGCC repeat RNA. - Functional characterization and disease relevance of selected RBPs. - Tool for detection and diagnostics of GGGGCC repeat RNA. - Disease relevance of stress induced misincorporation of amino acids in TDP-43.
Significance for science
During the duration of the project we have published nine original research papers, one review and one commentary. All together they have 395 citations (source Scopus) to date. We also had several dozen poster presentations and talks at various conferences as well as some invited lectures. All these activities and achievements have been noted in COBISS.
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. One such is getting involved with the Project MinE consortium, whose goal is to determine the genetic causes of ALS. We contributed more than 150 DNA samples from Slovenian ALS patients. As a part of this consortium we were also coauthors on a paper published in Nature Genetics (van Rheenen et al, Nature Genetics 2016). We have also been involved with ENCALS (European Network for the Cure of ALS) and we have been entrusted to organize the 2017 conference. Young postdoctoral scientists and up two 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. One PhD student also spent one year at the UC San Diego laboratory of prof. dr. Don Cleveland 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 medical professionals at the Slovenian psychogeriatric meeting in 2016.
Most important scientific results Annual report 2013, 2014, 2015, final report
Most important socioeconomically and culturally relevant results Annual report 2013, 2014, 2015, final report
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