Blocking the FKBP12 induced dendrimeric burst in aberrant aggregation of α-synuclein by using the ElteN378 synthetic inhibitor.
FKBP12 inhibitor
PD drug
Parkinson’s disease
amyloid aggregation
α-synuclein
Journal
Journal of enzyme inhibition and medicinal chemistry
ISSN: 1475-6374
Titre abrégé: J Enzyme Inhib Med Chem
Pays: England
ID NLM: 101150203
Informations de publication
Date de publication:
Dec 2019
Dec 2019
Historique:
entrez:
25
9
2019
pubmed:
25
9
2019
medline:
24
12
2019
Statut:
ppublish
Résumé
α-Synuclein (α-syn), a disordered cytoplasmatic protein, plays a fundamental role in the pathogenesis of Parkinson's disease (PD). Here, we have shown, using photophysical measurements, that addition of FKBP12 to α-syn solutions, dramatically accelerates protein aggregation, leading to an explosion of dendritic structures revealed by fluorescence and phase-contrast microscopy. We have further demonstrated that this aberrant α-syn aggregation can be blocked using a recently discovered non-immunosuppressive synthetic inhibitor of FKBP12, ElteN378. The role of FKBP12 and of ElteN378 in the α-syn aggregation mechanism has been elucidated using molecular dynamics simulations based on an effective coarse-grained model. The reported data not only reveal a new potent synthetic drug as a candidate for early stage treatment of α-syn dependent neurodegenerations but also pave the way to a deeper understanding of the mechanism of action of FKBP12 on α-syn oligomeric aggregation, a topic which is still controversial.
Identifiants
pubmed: 31547734
doi: 10.1080/14756366.2019.1667342
pmc: PMC6764402
doi:
Substances chimiques
1-(2-oxo-2-phenylacetyl)-N-(3-phenylpropyl)piperidine-2-carboxamide
0
Dendrimers
0
Piperidines
0
Protein Aggregates
0
alpha-Synuclein
0
Tacrolimus Binding Protein 1A
EC 5.2.1.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
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