Heterotypic amyloid interactions as modulators of selective cellular vulnerability

It is currently not known what determines the selective neuronal
vulnerability of amyloids in neurodegenerative pathologies: we do
not understand how amyloids interact with other cellular components,
whether these interactions are specific, and how these interactions
result in cell-specific toxic phenotypes.
Our lab has played a crucial role in elucidating how aggregationprone
regions drive the self-assembly of amyloid aggregates. We
hypothesise that the same mechanism that drives the homotypic
assembly of amyloids might also drive heterotypic interactions of
amyloids with homologous sequence segments in other proteins.
Such heterotypic aggregation could interfere with the normal function
of these proteins and could explain the specific spatio-temporal
emergence and spreading of aggregates in the brain.
The combination of experimental limitations and the lack of a
structural-molecular hypothesis directing the search has made finding
interaction partners of amyloids challenging. We propose to create a
new structure-based method to search for specific interaction
partners of amyloids and validate the method in vitro and in vivo.
Protein aggregation plays a crucial role in neurodegenerative
diseases, therefore identifying heterotypic aggregation partners of
amyloids will provide new angles at understanding and eventually
treating these conditions.