Molecular mechanisms of TDP-43 mediated neurodegeneration

Tar DNA binding protein of 43 kDa (TDP-43) has been identified as the major disease protein in cellular aggregates found in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). TDP-43 positive aggregates are also found in other neurodegenerative disorders including Alzheimer's, Parkinson's and Huntington's disease, thereby defining a novel proteinopathy. Mutations in the encoding TARDBP gene characterise heritable and sporadic cases of ALS and FTLD and recent studies in flies, fish and mice reveal that too much or not enough available TDP-43 protein can both contribute to disease onset and progression. TDP-43 proteinopathy is associated with faulty communication between nerve cells, which precede behavioural defects and progressive age-related degeneration of these nerve cells. However, the molecular mechanisms underlying neurodegeneration remain elusive. Our hypothesis is, and our preliminary data suggest, that TDP-43 regulates dSarm/Sarm1 and Hiw/mycBP2, as target proteins that have been shown to mediate an active autodestruction program. Our hypothesis predicts that TDP-43 mediated deregulation of these proteins causes degeneration of nerve cells starting with destruction of their contact points and axonal extensions and proceeding to the cell body itself, thereby causing "dying back-like" neurodegeneration. Here we propose to use animal and cell culture models to test this hypothesis and to dissect the molecular mechanisms by which TDP-43 regulates dSarm/Sarm1 and Hiw/mycBP2. We also aim to identify ways to rescue disease formation in a fly model of TDP-43 related neurodegeneration, and to translate these findings into the human disease condition by detecting changes in RNA and protein expression levels of human dSarm/Sarm1 and Hiw/mycBP2 homologues. Given that TDP-43 proteinopathy characterises several neurodegenerative disorders, including dementia, the expected findings will be of general relevance and application as they likely identify novel biomarkers and therapeutic targets for TDP-43 related neurodegeneration.

Tar DNA binding protein of 43 kDa (TDP-43) has been identified as the major disease protein present in cytoplasmic inclusions in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD), as well as in other neurodegenerative disorders including Alzheimer's, Parkinson's and Huntington's disease, thereby defining a novel proteinopathy. Dominant missense mutations in the encoding TARDBP gene characterise both familial and sporadic cases of ALS and FTLD, and recent studies in Drosophila, zebrafish and mice reveal that both loss and toxic gain of TDP-43 function contribute to disease onset and progression. TDP-43 proteinopathy is associated with synaptic defects which precede behavioural abnormalities and progressive age-related neurodegeneration. However, the molecular mechanisms underlying neurodegeneration remain elusive. Our hypothesis is, and our preliminary data suggest, that TDP-43 regulates dSarm/Sarm1 and Hiw/mycBP2 that mediate an active autodestruction program causing dying back-like neurodegeneration. Here we propose to use animal and cell culture models to test this hypothesis and to dissect the molecular mechanisms by which TDP-43 regulate dSarm/Sarm1 and Hiw/mycBP2. We also aim to identify ways to rescue disease formation in a Drosophila model of TDP-43 related neurodegeneration, and to translate these findings into the human disease condition by detecting RNA/protein changes for human homologues of the autodestruction pathway. Given that TDP-43 proteinopathy characterises several neurodegenerative disorders, including dementia, the expected findings will be of general relevance and application as they likely identify novel biomarkers and therapeutic targets for TDP-43 related neurodegeneration.

In a society with a growing population of elderly people, neurodegenerative disorders are becoming more and more abundant. Our research into the causes of neurodegeneration will significantly contribute to our understanding of these devastating diseases. The research proposed here will identify genes, and functional pathways, that are critically important in mediating neurodegeneration. The new information gained from the research of this proposal will make a significant contribution to a novel approach for the identification of biomarkers and therapeutic targets for neurodegenerative diseases. In addition, our insights gained into the causes and mechanisms underlying age-related neurodegeneration will inform strategies for improving healthy ageing and hence enhancing quality of life, while minimising the need for health and social care during ageing. The beneficiaries, listed below, will be both international and UK based.

Medical profession, charities and pharmaceutical industry
TDP-43 aggregates define a novel proteinopathy and have been found in several neurodegenerative diseases, including dementia. Thus, definition of the molecular and cellular mechanisms underlying TDP-43 related neurodegeneration, will identify genes, and functional pathways, that are critically important in pathogenesis. This in turn will lead to the identification of biomarkers and therapeutic targets for the early diagnosis and targeted treatment of TDP-43 related neurodegeneration. Thus, results from our research will inform the medical profession for clinical research, as well as charities for future strategies. It will also guide the pharmaceutical profession and on a longer shot pharmaceutical industry, to identify or generate drugs and compounds that can be used for the targeted treatment of TDP-43 related neurodegeneration but likely also other degenerative disorders.

Government and general public
Novel information concerning fundamental processes by which aberrant function of TDP-43 causes progressive neurodegeneration can ultimately lead to strategies for the early diagnosis and targeted treatment of TDP-43 related neurodegeneration. Hence it has the potential to enhance quality of life, while minimising the need for health and social care during ageing. Thus, the ability to identify biomarkers and therapeutic targets for the early diagnosis and targeted treatment of TDP-43 related neurodegeneration will affect government policies such as the UK government's dementia strategy and to support an ageing UK population. Important measures of the new strategy include providing support to people to plan earlier for their longer lives and making sure that services are suitable when the time comes to use them. The provision of new and novel information that will contribute to an understanding of the molecular and cellular pathways involved in TDP-43 related neurodegeneration, and therefore potential therapeutic targets, will help to refine and target these strategies to an ageing UK population and for the human population as a whole.