Abstract
(English)
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In response to paragraph 6.1 of the QoL Work Program, it is proposed to show that in various slow neurodegenerative diseases protein misfolding causes early changes in intracellular function, which serve as important pathogenetic markers of disease onset and progression. Focus will be on Parkinson's, Huntington's and prion diseases, but the project will also have impact on other neurodegenerative disorders of aging. In these disorders, there is currently an urgent need for methods that can identify early cell pathology and monitor treatment effects at the cellular level. Using a multidisciplinary approach, the objectives are to reveal, sequentially, in tissue culture, transgenic animals and in cells derived from patients, the early stages of mutant protein aggregate formation and its consequences. Emphasis will be on parameters of neuronal dysfunction, but changes in blood will also be demonstrated as early indicators of neuronal disease lymphocytes in mice and men exhibiting neurodegeneration. Therapeutic strategies to intervene in protein misfolding will be tested, with the aim to transfer this knowledge to clinical applications.
This proposal includes basic molecular science and its translation to clinical application, especially with the development of pathogenetically relevant diagnostic markers. This is particularly relevant to 6.1 of the QoL Work Program of FP5, as it aims at reducing the impact of incurable, slowly progressing and disabling neurodegenerative disorders, by facilitating the development of treatments that reduce their morbidity by delaying their onset or halting their progression. The team's expertise includes cell and molecular biology, protein engineering, clinical neuropathology, and clinical neuroscience.
We envisage 4 multidisciplinary Work Packages:
1. Cell culture models of slow neurodegeneration due to misfolded proteins.
2. Slow neurodegeneration due to misfolded proteins in animals.
3. Peripheral tissue changes due to misfolded proteins correlated to slow degeneration in the central nervous system.
4. Intervention in cell pathology caused by misfolded proteins.
The consortium will create model systems for Parkinson's, Huntington's and prion diseases using neuronal cells and transgenic mice. In these models, protein aggregate formation will be monitored in neurons. Changes in cell structure and biochemistry will be followed and defects in neural connections, transmitter release, neuronal firing and behaviour examined. These changes will be related to the extent and nature of protein aggregate formation. The pathological findings will be correlated to changes in peripheral blood lymphocytes of mice and humans, as well as on muscle biopsies from affected patients. New pharmacological approaches to limit protein misfolding and inhibit development of cell pathology both in neurons and peripheral tissue will be developed. Modification of the peripheral early markers and, neuronal dysfunction and degeneration will be examined during the pharmacological treatments to validate the markers and possibly identify agents of therapeutic interest.
Age-related disorders of the nervous system such as Alzheimer's, Huntington's and Parkinson's diseases, and transmissible encephalopathies caused by prions are associated with changes in the conformation of proteins expressed in nerve cells. These diseases share in common the formation of misfolded proteins and the accumulation of aggregates and deposits in brain. The ultimate goal is to use detection of protein aggregates or other early markers in easily accessible tissues as early diagnostic, prognostic, and therapeutic indicators of neuronaldisease in Parkinson's, Huntington's and prion diseases.
Using cell cultures, living animals and clinical materials, the main objectives of this proposal are:
1) To define the pathogenetic significance of protein misfolding and aggregation and, to identify and characterize concomitant changes in cell structure and metabolism as early signs of neurodegeneration;
2) To validate in accessible tissues such as blood, these early, biologically relevant markets as predicting the onset and progression of brain pathology;
3) To test pharmacological treatments using the validated markers.
Determination of the role of protein aggregates in the pathogenesis of neurodegenerative diseases.
Demonstrations that misfolded protein aggregates can be pivotal in the pathogenesis of several neurodegenerative diseases of aging, and that detection of protein aggregates, and their consequences, in peripheral tissues can be used as markers for the early detection and diagnosis. The transfer of this knowledge to clinical applications - specifically the use of aggregate formation and its consequences as biomarkers for disease progression and response to treatment.
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