Enhanced Clearance of Neurotoxic Misfolded Proteins by the Natural Compound Berberine and Its Derivatives.
Amyotrophic Lateral Sclerosis
/ drug therapy
Autophagy
/ drug effects
Berberine
/ pharmacology
Biological Products
/ pharmacology
Cell Line
Frontotemporal Dementia
/ drug therapy
Humans
Molecular Chaperones
/ genetics
Mutant Proteins
/ genetics
Neurotoxicity Syndromes
/ drug therapy
Proteasome Endopeptidase Complex
/ drug effects
Protein Aggregation, Pathological
/ drug therapy
Proteostasis Deficiencies
/ drug therapy
amyotrophic lateral sclerosis
autophagy
berberine
frontotemporal dementia
misfolding
neurodegeneration
proteasome
protein aggregation
spinal and bulbar muscular atrophy
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
13 May 2020
13 May 2020
Historique:
received:
29
04
2020
revised:
08
05
2020
accepted:
11
05
2020
entrez:
17
5
2020
pubmed:
18
5
2020
medline:
13
2
2021
Statut:
epublish
Résumé
Accumulation of misfolded proteins is a common hallmark of several neurodegenerative disorders (NDs) which results from a failure or an impairment of the protein quality control (PQC) system. The PQC system is composed by chaperones and the degradative systems (proteasome and autophagy). Mutant proteins that misfold are potentially neurotoxic, thus strategies aimed at preventing their aggregation or at enhancing their clearance are emerging as interesting therapeutic targets for NDs. We tested the natural alkaloid berberine (BBR) and some derivatives for their capability to enhance misfolded protein clearance in cell models of NDs, evaluating which degradative pathway mediates their action. We found that both BBR and its semisynthetic derivatives promote degradation of mutant androgen receptor (ARpolyQ) causative of spinal and bulbar muscular atrophy, acting mainly via proteasome and preventing ARpolyQ aggregation. Overlapping effects were observed on other misfolded proteins causative of amyotrophic lateral sclerosis, frontotemporal-lobar degeneration or Huntington disease, but with selective and specific action against each different mutant protein. BBR and its analogues induce the clearance of misfolded proteins responsible for NDs, representing potential therapeutic tools to counteract these fatal disorders.
Sections du résumé
BACKGROUND
BACKGROUND
Accumulation of misfolded proteins is a common hallmark of several neurodegenerative disorders (NDs) which results from a failure or an impairment of the protein quality control (PQC) system. The PQC system is composed by chaperones and the degradative systems (proteasome and autophagy). Mutant proteins that misfold are potentially neurotoxic, thus strategies aimed at preventing their aggregation or at enhancing their clearance are emerging as interesting therapeutic targets for NDs.
METHODS
METHODS
We tested the natural alkaloid berberine (BBR) and some derivatives for their capability to enhance misfolded protein clearance in cell models of NDs, evaluating which degradative pathway mediates their action.
RESULTS
RESULTS
We found that both BBR and its semisynthetic derivatives promote degradation of mutant androgen receptor (ARpolyQ) causative of spinal and bulbar muscular atrophy, acting mainly via proteasome and preventing ARpolyQ aggregation. Overlapping effects were observed on other misfolded proteins causative of amyotrophic lateral sclerosis, frontotemporal-lobar degeneration or Huntington disease, but with selective and specific action against each different mutant protein.
CONCLUSIONS
CONCLUSIONS
BBR and its analogues induce the clearance of misfolded proteins responsible for NDs, representing potential therapeutic tools to counteract these fatal disorders.
Identifiants
pubmed: 32414108
pii: ijms21103443
doi: 10.3390/ijms21103443
pmc: PMC7279252
pii:
doi:
Substances chimiques
Biological Products
0
Molecular Chaperones
0
Mutant Proteins
0
Berberine
0I8Y3P32UF
Proteasome Endopeptidase Complex
EC 3.4.25.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Fondazione Telethon
ID : GGP14039
Organisme : Fondazione Telethon
ID : GGP19128
Organisme : Kennedy's disease association
ID : 2018 Grant
Organisme : Fondazione Cariplo
ID : 2014-0686
Organisme : Fondazione Cariplo
ID : 2017_0747
Organisme : Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica
ID : ALS_HSPB8
Organisme : Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica
ID : ALS_Granulopathy
Organisme : Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica
ID : MLOpathy
Organisme : Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica
ID : Target-RAN
Organisme : AFM-Téléthon
ID : 16406
Organisme : Università degli Studi di Milano
ID : Piano di sviluppo UNIMI - linea B
Organisme : Università degli Studi di Milano
ID : Bando Straordinario per Progetti Interdipartimentali (Bando SEED 2019: #TDP-43-iPSC
Organisme : Ministero dell'Istruzione, dell'Università e della Ricerca
ID : PRIN 2015LFPNMN
Organisme : Ministero dell'Istruzione, dell'Università e della Ricerca
ID : 2017F2A2C5
Organisme : Ministero dell'Istruzione, dell'Università e della Ricerca
ID : Fondo per il Finanziamento delle Attività Base di Ricerca (FFABR)
Organisme : Agenzia Italiana del Farmaco, Ministero della Salute
ID : Co_ALS
Organisme : Ministero della Salute
ID : GR-2011-02347198
Organisme : Fondazione Regionale per la Ricerca Biomedica (FRRB) (Regione Lombardia
ID : TRANS_ALS, project nr. 2015-0023
Organisme : EU Joint Programme - Neurodegenerative Disease Research
ID : 01ED1601A, CureALS
Déclaration de conflit d'intérêts
The authors declare no conflict of interest.
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