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

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http://hdl.handle.net/10138/332776

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Hlushchuk , I , Ruskoaho , H , Domanskyi , A , Airavaara , M & Välimäki , M J 2021 , ' Domain-Independent Inhibition of CBP/p300 Attenuates alpha-Synuclein Aggregation ' , ACS chemical neuroscience , vol. 12 , no. 13 , pp. 2273-2279 . https://doi.org/10.1021/acschemneuro.1c00215

Title: Domain-Independent Inhibition of CBP/p300 Attenuates alpha-Synuclein Aggregation
Author: Hlushchuk, Irena; Ruskoaho, Heikki; Domanskyi, Andrii; Airavaara, Mikko; Välimäki, Mika J.
Contributor: University of Helsinki, Division of Pharmacology and Pharmacotherapy
University of Helsinki, Division of Pharmacology and Pharmacotherapy
University of Helsinki, Institute of Biotechnology
University of Helsinki, Drug Research Program
University of Helsinki, Division of Pharmacology and Pharmacotherapy
Date: 2021-07-07
Language: eng
Number of pages: 7
Belongs to series: ACS chemical neuroscience
ISSN: 1948-7193
URI: http://hdl.handle.net/10138/332776
Abstract: 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.
Subject: alpha-Synuclein
lysine acetyltransferase
bromodomain
Parkinson's disease
CBP
p300
BROMODOMAIN INHIBITOR
DISEASE
PROTEIN
1182 Biochemistry, cell and molecular biology
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