Projects / Programmes
Transport and RNA binding of TDP-43 and FUS - implications for ALS/FTLD spectrum of neurodegenerative disease
| 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 |
neurodegeneration, frontotemporal lobar degeneration, amyoptrophic lateral sclerosis, TDP-43, FUS, RNA
Researchers (26)
Organisations (5)
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
