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

Automated summary

Neurodegenerative diseases are associated with failed proteostasis and accumulation of insoluble protein aggregates. Inhibitors targeting CBP and p300 proteins may offer a promising approach to reduce alpha-synuclein aggregation. High-affinity CBP/p300 inhibitors could provide an effective means to prevent pathological accumulation of alpha-synuclein in dopaminergic neurons.