Descrizione del progetto
Il ruolo degli chaperone nei disturbi neurodegenerativi
Gli chaperone molecolari sono proteine implicate nel ripiegamento e nel dispiegamento delle molecole, incluse le proteine. È però scarsamente compreso il meccanismo di identificazione di aggregati proteici quali quelli implicati nella malattia di Alzheimer e nel morbo di Parkinson. L’obiettivo principale del progetto MicroSPARK, finanziato dall’UE, è chiarire il meccanismo con cui gli chaperone si indirizzano alle proteine di tipo amiloide e le scompongono. I ricercatori, avvalendosi di un approccio di spettroscopia a fluorescenza a singola molecola, analizzeranno i singoli complessi chaperone-aggregato, rivelando il meccanismo d’azione degli chaperone. I risultati apriranno la strada alla progettazione di nuovi modulatori a piccole molecole dell’attività degli chaperone per il trattamento dei disturbi neurodegenerativi.
Obiettivo
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.
Campo scientifico
Not validated
Not validated
- 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
Programma(i)
Argomento(i)
Meccanismo di finanziamento
MSCA-IF-EF-ST - Standard EFCoordinatore
CB2 1TN Cambridge
Regno Unito