Domain-Independent Inhibition of CBP/p300 Attenuates α-Synuclein Aggregation

Neurodegenerative diseases are associated with failed proteostasis and accumulation of insoluble protein aggregates that compromise neuronal function survival. In Parkinson’s disease, a major pathological finding is Lewy bodies neurites mainly composed phosphorylated aggregated α-synuclein fragments organelle membranes. Here, we analyzed series selective inhibitors acting on multidomain proteins CBP p300 contain both lysine acetyltransferase bromodomains responsible for the recognition enzymatic modification residues. By using high-affinity inhibitors, A-485, GNE-049, SGC-CBP30, explored role two closely related proteins, p300, as promising targets attenuation aggregation. Our data show CBP/p300 may alter course in primary mouse embryonic dopaminergic neurons. Hence, drug-like provide an effective approach development drug candidates preventing aggregation via systemic administration.