After a protein is created in the cell, it must be folded into the right conformation in order to function correctly. A complex set of mechanisms is focused on (a) achieving correct folding and (b) removing misfolded proteins when the process fails. Research into protein misfolding is weighted heavily to the consideration of the comparatively few proteins that form solid aggregates when misfolded, largely because this is an evident and measurable form of pathology that is demonstrably a cause of pathology in conditions such as Alzheimer's disease and the varied forms of amyloidosis. What about all of the other misfolded proteins, however, those that remain soluble? Researchers here point out that hundreds of different misfolded proteins can be found in the aged rat brain, and we might reasonably think that their collective role in neurodegeneration is significant.
Many studies have found that the proteostasis network, which functions to keep proteins properly folded, is impaired with age, suggesting that there may be many proteins that incur structural alterations with age. Here, we have used limited proteolysis mass spectrometry (LiP-MS) to identify proteins that vary in structure in the hippocampus of aged rats with or without cognitive impairment, which we have defined as CASC proteins.
We identified 215 CASC proteins in the CA1 hippocampal region. Research in aging, dementia, and neurodegenerative disease has long made a connection between these disease processes and protein misfolding; however, emphasis has historically been paid to proteins that form amyloids or other insoluble aggregates. We have focused on the soluble fraction of the hippocampal proteome and used a methodology that can sensitively detect subtle changes in protein structure. The results enable us to conclude that protein misfolding is perhaps a more pervasive feature in cognitive decline than previously appreciated and that many of these misfolded forms persist as soluble species.
This finding suggests that there may be previously unidentified avenues for potential therapeutic targets and diagnostic biomarkers for cognitive decline than the small subset of amyloid-forming proteins frequently studied. Of course, these interventions would need to be conformation specific, creating additional opportunities and challenges.
Link: https://doi.org/10.1126/sciadv.adt3778
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