Targeting protein aggregate co-pathologies in neurodegeneration: a viable therapeutic strategy?

proteinopathy models show interactions between pathological forms of these proteins that increase protein aggregation and neurotoxicity, suggesting distinct mechanisms underlying co-pathologies that play a significant role in neurodegeneration. In this review, we describe the frequency of protein co-pathologies across neurodegenerative diseases and preclinical work demonstrating pathological protein synergies that exacerbate protein aggregation and toxicity. We also discuss granulovacuolar degeneration bodies, proteolytically active lysosomal structures that are induced by either pathological tau or α-synuclein accumulation, as an example of a shared cellular response to, and link between, distinct protein pathologies. Finally, we highlight interventional clinical trials which target multiple pathologies and/or specifically target co-pathologies in neurodegenerative diseases, noting that current preclinical and clinical research is limited and this line of investigation should be pursued more vigorously. In all, we find that protein co-pathologies are frequently observed in the brains of common neurodegenerative diseases and serve as important future therapeutic targets for combatting neurodegeneration across clinically distinct diseases.