Proteostasis study in Huntington disease mouse model:
The motivation for choosing this model is that in this mouse line there is a clear progression of the aggregates with aging and it is a clear difference in the aggregation pattern found in different cell-types, specially two main cell-types in the brain; Neurons and Glia, both with important roles in the development of the disease.
Huntington’s disease belongs to the polyglutamine diseases, this group of neurodegenerative disorders is characterized by the expansion of the trinucleotide repeat CAG, encoding for glutamine. Polyglutamine expansions induce protein aggregation that ultimately/or simultaneously disturbs cellular protein homeostasis. The onset of the disease is proportional to the number of repeats, but generally appears in middle/elderly-aged individuals and the aggregates of Huntingtin (Htt) become more frequent with age in all cases. One possible explanation for this is that younger neurons are able to clear cytotoxic proteins more efficiently than older neurons, this might occur because the degradation machinery, including the UPS or autophagy, might become less efficient with age. Despite extensive exploration of these pathways, it remains elusive which are the specific changes on its components, or which are the specific factors that modulate Htt aggregation during the aging process. We are using cell-type specific proteomes to explore the protein landscape in neurons and glia with the aim to elucidate some of the molecules/pathways involved in protein aggregation and clearance.