Title of project or programme

Molecular mechanisms of neurodegeneration

Principal Investigators of project/programme grant
Title Forname Surname Institution Country
Dr Michel Goedert MRC Laboratory of Molecular Biology UK
Address of institution of lead PI
Institution MRC Laboratory of Molecular Biology
Street Address Hills Road
City Cambridge
Postcode CB2 0QH
Country
  • United Kingdom
Source of funding information

Medical Research Council

Total sum awarded (Euro)

8486873.77

Start date of award

01-04-2005

Total duration of award in months

60

The project/programme is most relevant to
  • Alzheimer’s disease and other dementias
  • Parkinson’s disease
  • Neurodegenerative disease in general
Keywords
Research abstract in English

Considerable progress has been made in characterizing the molecular neuropathology of dementias and movement disorders. Most cases of disease associated with pathological filament formation are now accounted for by either tau or alpha-synuclein deposits. The discoveries of mutations in the tau gene in inherited forms of frontotemporal dementia and the alpha-synuclein gene in inherited forms of Parkinson’s disease have established that the pathway leading from soluble to filamentous protein, be it tau or alpha-synuclein, is central to the aetiology and pathogenesis of these familial cases of disease. The same is probably true of the much more common sporadic diseases, such as Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration and Pick’s disease. A detailed understanding of the mechanisms underlying the assembly of tau and alpha-synuclein into abnormal filaments could provide novel targets for putative drugs It is therefore important to understand as much as possible about these mechanisms. In the future, the mouse line transgenic for human P301S tau will be used to identify genetic and pharmacological modifiers (enhancers and suppressors) of the neurodegenerative phenotype. This will lead to a comprehensive test of the hypothesis that hyperphosphorylation is important for the assembly of tau into filaments and neurodegeneration. We are in the process of investigating the relevance of individual phosphorylation sites by producing lines of transgenic mice with mutations in these sites. We will assess the relevance of individual protein kinases by using knock-out mice and specific protein kinase inhibitors. The proposed work is based on the hypothesis that the hyperphosphorylation of tau contributes directly to disease. In parallel, we will use an unbiased approach making use of mutagenesis with ethyl N-nitrosourea, to identify disease modifiers. In addition, we have recently shown that experimental tauopathy can be transmitted and that it spreads between adjacent brain regions in a tau-dependent manner. This work has opened up new avenues for the understanding of tauopathy. In the future, we will pursue a similar strategy with respect to alpha-synuclein and its involvement in neurodegeneration. This field is younger and much remains to be learned. We are concentrating on understanding the mechanisms by which alpha-synuclein assembles into filaments and on developing transgenic mouse models for the human alpha-synucleinopathies. We also wish to develop experimental systems by which to study the spreading of alpha-synuclein pathology between cells.

Lay Summary

    Principal Investigators

    Dr M Goedert

    Institution

    MRC Laboratory of Molecular Biology

    Contact information of lead PI

    Country

    United Kingdom

    Title of project or programme

    Molecular mechanisms of neurodegeneration

    Source of funding information

    MRC

    Total sum awarded (Euro)

    € 10,348,021

    Start date of award

    01/10/2011

    Total duration of award in years

    5.0

    The project/programme is most relevant to:

    Alzheimer's disease and other dementias | Parlinson's disease and PD-related disorders

    Keywords

    Neurodegenerative diseases| tau protein| alpha-synuclein| Alzheimer's disease| Parkinson's disease| frontotemporal dementia| progressive supranuclear palsy| corticobasal degeneration| Pick's disease| dementia with Lewy bodies| multiple system atrophy

    Research Abstract

    Considerable progress has been made in characterizing the molecular neuropathology of dementias and movement disorders. Most cases of disease associated with pathological filament formation are now accounted for by either tau or alpha-synuclein deposits. The discoveries of mutations in the tau gene in inherited forms of frontotemporal dementia and the alpha-synuclein gene in inherited forms of Parkinson’s disease have established that the pathway leading from soluble to filamentous protein, be it tau or alpha-synuclein, is central to the aetiology and pathogenesis of these familial cases of disease. The same is probably true of the much more common sporadic diseases, such as Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration and Pick’s disease. A detailed understanding of the mechanisms underlying the assembly of tau and alpha-synuclein into abnormal filaments could provide novel targets for putative drugs It is therefore important to understand as much as possible about these mechanisms. In the future, the mouse line transgenic for human P301S tau will be used to identify genetic and pharmacological modifiers (enhancers and suppressors) of the neurodegenerative phenotype. This will lead to a comprehensive test of the hypothesis that hyperphosphorylation is important for the assembly of tau into filaments and neurodegeneration. We are in the process of investigating the relevance of individual phosphorylation sites by producing lines of transgenic mice with mutations in these sites. We will assess the relevance of individual protein kinases by using knock-out mice and specific protein kinase inhibitors. The proposed work is based on the hypothesis that the hyperphosphorylation of tau contributes directly to disease. In addition, we have recently shown that experimental tauopathy can be transmitted and that it spreads between adjacent brain regions in a tau-dependent manner. This work has opened up new avenues for the understanding of tauopathy. In the future, we will pursue a similar strategy with respect to alpha-synuclein and its involvement in neurodegeneration. This field is younger and much remains to be learned. We are concentrating on understanding the mechanisms by which alpha-synuclein assembles into filaments and on developing transgenic mouse models for the human alpha-synucleinopathies.

    Lay Summary

    Alzheimer’s disease and Parkinson’s disease are the most common neurodegenerative diseases, affecting approximately 30 million people worldwide. Existing therapies are at best symptomatic. The symptoms of Alzheimer’s disease (a dementing disorder) and Parkinson’s disease (a movement disorder) result from the dysfunction and degeneration of specific types of nerve cells in particular brain regions. These nerve cells are characterized by the presence of abnormal filamentous deposits. Similar deposits also characterize several other neurodegenerative diseases, such as progressive supranuclear palsy, corticobasal degeneration, Pick’s disease and other frontotemporal dementias, dementia with Lewy bodies and multiple system atrophy. Collectively, they account for the vast majority of cases of neurodegenerative disease in man. Our previous work was instrumental in establishing that the filamentous deposits characteristic of these diseases are made of either the microtubule-associated protein tau or the protein alpha-synuclein. It is now widely believed that their formation causes nerve cell degeneration. Our current work is aimed at understanding the mechanisms by which the normally soluble tau and alpha-synuclein proteins assemble into abnormal filaments. To this effect, we are developing experimental models of tau and alpha-synuclein deposition. In due course, this work may lead to the development of mechanism-based therapies for the tauopathies and the alpha-synucleinopathies.

    Further information available at:

Types: Investments > €500k
Member States: United Kingdom
Diseases: Alzheimer's disease & other dementias, Neurodegenerative disease in general, Parkinson's disease & PD-related disorders
Years: 2011
Database Categories: N/A
Database Tags: N/A

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