Protein aggregation: From descriptive to quantitative understanding of protein aggregation and clearance in neurodegenerative diseases.

Despite the remarkable progress that has been made in establishing the link between protein aggregation and neurodegenerative diseases, several fundamental questions regarding the sequence, molecular and cellular factors that govern this process and its role in disease pathogenesis remain unanswered. Furthermore, common approaches to investigating disease-associated proteins have focused primarily on investigating one form of the molecule at a time, thus ignoring the complexity and diversity of these proteins and their interactions with homologeous proteins. This knowledge gap combined with the limitation of the current experimental approaches and the absence of models that recapitulate all cardinal features of the disease have contributed to the lack of new therapeutic strategies to treat and/or slow the progression of neurodegenerative diseases such as Alzheimer’s disease, Huntington’s disease and Parkinson’s disease. We believe that the development of good disease models will require more in depth understanding of protein aggregation and clearance under conditions that recapitulate the proteome complexity of these proteins under physiological-like conditions and within a reasonable timeframe.

Research Priorities
  •  Develop novel approaches to investigate protein aggregation under conditions that take into account the natural and pathologic chemcial diversity of the disease-associated proteins
  • Exploit single molecule FRET techniques to elucidate the structural properties of first misfolded amyloidogenic interamediates on the pathway to amyloid formation under physiological-like conditions and identify molecules that target protein misfolding and/or early stages of aggregation.
  • Exploit novel imaging techniques and emerging technologies to investigate the dyanmics of amyloid formation and clearance.
  • Investigate the kinetics and mechanisms of amyloid fibril diassociation and clearance and identify strategies to accelerate amyloid disassociation and clearance in vitro and in vivo.
  • Elucidate the sequence determinants of protein misfolding and aggregation with an emphasis on comparing the structural and aggregation proteins implicated in neurodegenerative disease to their non-aggregating homologeous proteins (e.g. human and mouse/rat alpha-synulcein).