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Projects / Programmes source: ARIS

Targeting protein phase separation and aggregation in neurodegenerative TDP-43 proteinopathies

Research activity

Code Science Field Subfield
3.03.00  Medical sciences  Neurobiology   

Code Science Field
3.01  Medical and Health Sciences  Basic medicine 
Keywords
TDP-43, stress granules, aggregation, amyotrophic lateral scerosis, frontotemporal dementia, neurodegeneration
Evaluation (rules)
source: COBISS
Points
2,130.82
A''
350.75
A'
1,093.46
A1/2
1,646.61
CI10
14,994
CImax
1,407
h10
53
A1
7.74
A3
1.76
Data for the last 5 years (citations for the last 10 years) on April 18, 2024; A3 for period 2018-2022
Data for ARIS tenders ( 04.04.2019 – Programme tender, archive )
Database Linked records Citations Pure citations Average pure citations
WoS  293  17,831  16,720  57.06 
Scopus  287  19,046  17,906  62.39 
Researchers (11)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  23399  PhD Tomaž Curk  Computer science and informatics  Researcher  2021 - 2024  253 
2.  35424  PhD Tomaž Hočevar  Computer science and informatics  Researcher  2021 - 2022  30 
3.  16345  PhD Tomaž Marš  Neurobiology  Researcher  2021 - 2024  345 
4.  21397  PhD Helena Motaln  Biochemistry and molecular biology  Researcher  2021 - 2024  207 
5.  56246  Jerneja Nimac  Neurobiology  Junior researcher  2022 - 2024  25 
6.  57702  Neža Pajek Arambašič  Computer science and informatics  Researcher  2023 - 2024 
7.  28351  PhD Sergej Pirkmajer  Neurobiology  Researcher  2021 - 2024  451 
8.  57847  Klementina Polanec  Neurobiology  Researcher  2023 - 2024 
9.  15813  PhD Boris Rogelj  Neurobiology  Head  2021 - 2024  412 
10.  15600  MSc Maja Šimaga    Technical associate  2021 - 2024 
11.  38850  PhD Nives Škorja Milić  Neurobiology  Researcher  2023 - 2024  17 
Organisations (3)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0106  Jožef Stefan Institute  Ljubljana  5051606000  90,664 
2.  0381  University of Ljubljana, Faculty of Medicine  Ljubljana  1627066  48,203 
3.  1539  University of Ljubljana, Faculty of Computer and Information Science  Ljubljana  1627023  16,235 
Abstract
Neurodegenerative disorders represent an increasing threat to the world public health and economy. There are no drugs that can substantially slow or prevent disease progression. Our understanding of the molecular basis of these diseases thus urgently needs to be improved. Hence, we are committed to identify novel drug targets for possible development of more effective therapies. Majority of neurodegenerative disorders are characterised by proteinaceous aggregates (proteinopathies) that accumulate in either the extracellular milieu or intracellular compartments of the affected cells. Frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and to an increasing extent also Alzheimer’s disease (AD), are characterised by cytoplasmic aggregates of TDP-43, a nuclear RNA-binding protein (RBP). It is generally accepted that under stress conditions within the cells TDP-43, along with some other RBPs, other proteins and RNAs, coalesces into cytoplasmic membraneless organelles, the so-called stress granules (SG). SGs allow the cell to cope with stress by transiently stalling normal protein translation, moving towards synthesis of cytoprotective proteins, and restoring other protein translation again as stress passes and the SGs dissolve. But during chronic stress exposure, such as in ageing, when defects in normal cellular processes accumulate, TDP-43 may start forming irreversible and insoluble aggregates resulting in degeneration of neuronal cells. This raises one of the most important questions in the field - What drives nuclear protein TDP-43 to accumulate and aggregate in the cytoplasm? The answer most probably lies in the changes of TDP-43 de novo expression, modifications, localization and/or degradation that are all afflicted by changes in TDP-43 protein-protein interactions. This project will thus focus on changes of the TDP-43 interactome emerging as TDP-43 shifts from soluble to coalesced state within SGs upon oxidative stress and, conversely, SGs disassembly following removal of oxidative stress. Our aim is to identify and mechanistically/pathologically characterise stress-related protein interactors of TDP-43, to increase the understanding of neurodegenerative disease mechanisms in order to facilitate the search for therapeutic targets. To this end the proposed project has three objectives: 1. Determine transient changes in the interactome of TDP-43 following oxidative stress and return to normal state. 2. Determine disease relevance of stress-related interactors of TDP-43. 3. Gauge the therapeutic potential of modulating selected interactors on TDP-43 aggregation. We will be implementing cutting-edge procedures, such as APEX2 for the identification of dynamic in vivo protein-protein interactions, which will enable us taking instantaneous “interactome snapshots” of TDP-43 to determine changes in its interactome upon oxidative stress exposure and return to normal state. These will provide us with far more exact insight into molecular processes leading to aggregation of TDP-43. The PI and international collaborators have extensive experience in the molecular mechanisms of ALS and FTD to execute this quite complex and ambitious project. The PI has pioneered in a number of topics of the ALS and FTD research, by extensively characterizing the disease related mechanisms of TDP-43, FUS and other genes, especially with regards to their perturbed RNA biology, nuclear transport, turnover and pathology. Our group was also one of the first pointing to perturbed stress granule regulation in these diseases. Therefore, we are confident to successfully carry out the research presented in this proposal. In conclusion, we are confident that investment into this research will bring us closer to understanding the disease processes and facilitate the search for treatments of TDP-43-associated disorders and other similar proteinopathies.
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