Marie Curie Research Training Network
TRACKS
Transglutaminases: role in pathogenesis, diagnosis and therapy (TRACKS)
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Objective 1 : Role of TGase in Neurodegenerative Diseases
A proteomics approach will be used to identify the protein interactions and the degree and sites of protein crosslinking in insoluble aggregates of clinical specimens, cell and experimental models. A further objective is to develop controllable (using inducible expression of proteins) cellular models for TG2-mediated inclusion formation.
The cytopathic effects resulting from inclusion growth can thus be monitored at the cell and molecular level with respect to protein content (using proteomics) and effects on organelle trafficking, cytoskeletal arrangement and membrane stability and mobility. If the inclusions are toxic and TG is involved in this toxicity to the host cell, further experimentation with TG inhibitors will take place (Objective 4) using both cell and experimental models.
Protective agents, TG2 inducers or inhibitors would offer a possible path for further investigation and potential pharmacological intervention. Detection of crosslink (Objective 6) in cerebrospinal fluid can then be monitored as an early diagnostic tool of disease progression.
