Projects / Programmes
Nuclear transport defects in neurodegenerative diseases
| 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, amyotrophic lateral sclerosis, neurodegeneration, TDP-43, FUS, nuclear transport
Researchers (16)
Organisations (3)
Abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are devastating neurodegenerative diseases that represent two ends of a complex disease spectrum. Cytoplasmic mislocalization and aggregation of nuclear RNA binding proteins is one of the hallmark pathological features of ALS and FTLD, and suggests perturbance of nuclear transport mechanisms in their aetiology. In 95% of all ALS and 60% of FTLD patients the aggregating protein is TDP-43, thus defining the major part of the disease spectrum as TDP-43 proteinopathies. However, only a very small percentage of aggregation is actually caused by TDP-43 mutations. In order to understand the disease process and look for ways of treatment, discerning pathways that may bring about the aggregation of wildtype TDP-43 is one of the main focuses in the field of ALS and FTLD research. Current understanding is that changes in de novo synthesis levels, localization and turnover of TDP-43 may all have a role to play in ALS/FTLD.
This project aims to study the pathological role of TDP-43 and FUS mislocalization in the ALS/FTLD spectrum disorder through a use of novel isolation protocols and differential proteomics of neuronal nuclei from post-mortem tissues to determine differences between healthy and diseased nuclei. We will also look at the changes in binding partners of FUS and TDP-43 when they are mislocalized and/or aggregated. Finally, we want to take forward our discovery of phosphorylation of C-terminal tyrosine of FUS, by determining the possibility of this phosphorylation in ALS and FTLD, which could become a useful tool in understanding and diagnosing FUSopathies.
To this end the project has three objectives, each addressing specific question of nuclear transport pathogenicity.
1. Disease related changes in neuronal nuclear proteome.
2. Determination of cytoplasmic, nuclear and aggregate specific TDP-43 and FUS interactors.
3. Disease relevance of FUS phosphorylation and misaccumulation.
The proposed project will both be a development of new research directions through a de novo discovery of changes in the neuronal nuclear proteome in TDP-43 proteinopathies and FUS/TDP-43 interactome as well as the validation of a novel antibody against phosphorylated C-terminal tyrosine for prognosis of FUSopathies
Investment into this research may bring us closer to understanding the disease processes and facilitate the search for cures. It is also of importance that we will be using some of the newest cutting-edge procedures, such as nuclear proteomics and in vivo protein-protein interaction determination, which will provide far wider insight in general molecular process occurring in cell nuclei.
The PI and international collaborators have experience in the molecular mechanisms of ALS and FTLD, which is reflected in our high-impact publications in the field. We are also one of the first groups to alert to the possibility of nuclear transport disturbances in these diseases, therefore, we believe that we are very well positioned to carry out the research presented in this proposal.
Significance for science
ALS and FTLD are fatal neurological disorders for which there is no known cure. Recent findings including ours, strongly implicate the disturbances in nuclear transport processes in this spectrum disorder. Numerous other high-impact publications suggest the arising importance of nuclear transport-related processes in understanding other complex diseases and in the development of novel therapies. Reduction in the nuclear transport efficiency is also associated with ageing.
Investment into this research may bring us closer to understanding the disease processes and facilitate the search for cures. It is also of importance that we will be using some of the newest cutting-edge procedures, such as nuclear proteomics and protein-protein interaction determination, which will have far wider implications for studies of general molecular process occurring in cell nuclei.
The PI and international collaborators have experience in the molecular mechanisms of ALS and FTLD, which is reflected in our high-impact publications in the field. We are also one of the first groups to alert to the possibility of nuclear transport disturbances in these diseases, therefore, we believe that we are very well positioned to carry out the research presented in this proposal.
Significance for the country
With the ageing population neurodegenerative disorders are becoming one of the largest threats to public health and the economy worldwide. For example, a recent report by the England and Wales Office of National Statistics has shown that, for the first time and using a grouping based on that developed by the World Health Organisation, dementia has become the leading cause of death in the year 2015 (https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/bulletins/deathsregisteredinenglandandwalesseriesdr/2015). Despite half a century of advances in neuroscience, there are no drugs that significantly improve the course of any neurodegenerative disorder. Misdiagnosis is common and there are no definite early diagnostic tests that permit intervention before major disability develops. Dementia research funding is far behind spending on other serious diseases and dementia care costs are set to treble in the next 20 years (World Alzheimer’s Report 2010). Increased longevity and falling birth rates indicate that the pressure on the economy will shrink the funding even further just as the cost of care increases, which is unsustainable. With this in mind, countries like USA and UK are increasing their investment into neurodegeneration research even in the current times of economic instability and recession. For example, the federal budget of USA had a 60% increase for dementia research for 2016 and at the end of 2015 it was announced that UK’s first Dementia Research Institute will receive up to L150 million to drive forward research and innovation in fighting dementia.
The epidemiological and financial figures are stark but do not reflect the social impact of the neurodegenerative disease on patients, carers and their families. Neurodegenerative diseases are rightly feared because of the severe disability they cause and the terrible burden of care. This fear is compounded by the fact that many have a significant genetic component, raising the spectre that others in the family may become affected. The decline in cognition, limited mobility and altered behaviour are particularly challenging. The affected individual suffers a loss of autonomy and a sense of being a burden to others. Depression is very common and often difficult to treat. Although ALS is relatively rare, it is one of the most devastating disease. For example, it is the most common reason people seek euthanasia in countries where it is legalized. Although medication can provide symptomatic improvement, benefit is temporary and all of these conditions progress relentlessly. There is a pressing need to discover therapies that can slow or prevent disease progression.
Advances in our understanding of the molecular basis of these diseases present an imperative and exciting opportunity to identify novel druggable targets and develop more effective interventions.
Most important scientific results
Final report
Most important socioeconomically and culturally relevant results
Interim report,
final report
