Descripción del proyecto
La función de las chaperonas en los trastornos neurodegenerativos
Las chaperonas moleculares son proteínas involucradas en el plegamiento y despliegue de moléculas, incluidas las proteínas. Sin embargo, se sabe poco acerca del mecanismo de caracterización de agregados de proteínas como los que están implicados en las enfermedades de Alzheimer y de Parkinson. El objetivo principal del proyecto MicroSPARK, financiado con fondos europeos, es dilucidar el mecanismo por el cual las chaperonas tienen como diana y descomponen los tipos de proteínas amiloides. Los investigadores analizarán, con un método de espectroscopia de fluorescencia a nivel de molécula única, los complejos individuales chaperona-agregado, lo que revelará el mecanismo de acción de las chaperonas. Los resultados allanarán el camino para el diseño de nuevos moduladores de molécula pequeña de la actividad de las chaperonas en los trastornos neurodegenerativos.
Objetivo
A range of debilitating neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases, arise from the formation of amyloidogenic protein aggregates. Molecular chaperones can counteract aggregate formation, but their molecular action mechanisms remain poorly understood. This is chiefly due to the fundamental challenge of resolving heterogeneous and dynamic aggregating protein species in the presence of chaperones. In order to address this challenge and to advance our knowledge of chaperone action, I propose establishing µSPARK, a novel technology that will allow, for the first time, the unravelling of the detailed microscopic mechanisms by which chaperones target and disassemble amyloidogenic protein species in heterogeneous mixtures at the single-molecule level. These new insights will become possible through the first-time combination and seamless integration of two advanced technologies: (i) Miniaturized fluidic sorting devices and (ii) single-molecule fluorescence spectroscopy combined with three-colour coincidence detection. This will enable high-throughput single-particle interrogation of individual chaperone–aggregate complexes providing fundamentally new means for understanding key aspects of chaperone function. To demonstrate the new possibilities, µSPARK will be exploited to unravel the action mechanisms of heat-shock proteins in curtailing amyloid-β peptide and α-synuclein aggregation. This will provide new insights into proteostatic regulatory mechanisms in Alzheimer’s and Parkinson’s disease. The µSPARK technology will then be exploited to dissect—with high throughput and single-particle resolution—the molecular action mechanisms of small-molecule modulators that promote the inhibitory function of chaperones on protein aggregation. This will allow identifying new strategies to ameliorate aggregate toxicity and will pave the way for µSPARK to become a novel screening tool for drug development.
Ámbito científico
- medical and health sciencesbasic medicinepharmacology and pharmacydrug discovery
- medical and health sciencesbasic medicineneurologydementiaalzheimer
- natural sciencesphysical sciencesopticsspectroscopyemission spectroscopy
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- medical and health sciencesbasic medicineneurologyparkinson
Programa(s)
Régimen de financiación
MSCA-IF-EF-ST - Standard EFCoordinador
CB2 1TN Cambridge
Reino Unido