Background: Accumulation of misfolded proteins is a common hallmark of several neurodegenerative disorders (NDs) which results from a failure or an impairment of the proteinquality 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: 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: 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: BBR and its analogues induce the clearance of misfolded proteins responsible for NDs, representing potential therapeutic tools to counteract these fatal disorders.

Enhanced Clearance of Neurotoxic Misfolded Proteins by the Natural Compound Berberine and Its Derivatives / P. Rusmini, R. Cristofani, B. Tedesco, V. Ferrari, E. Messi, M. Piccolella, E. Casarotto, M. Chierichetti, M.E. Cicardi, M. Galbiati, C. Geroni, P. Lombardi, V. Crippa, A. Poletti. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1422-0067. - 21:10(2020 May 02). [10.3390/ijms21103443]

Enhanced Clearance of Neurotoxic Misfolded Proteins by the Natural Compound Berberine and Its Derivatives

Rusmini, Paola;Cristofani, Riccardo;Tedesco, Barbara;Ferrari, Veronica;Messi, Elio;Piccolella, Margherita;Casarotto, Elena;Chierichetti, Marta;Cicardi, Maria Elena;Galbiati, Mariarita;Crippa, Valeria;Poletti, Angelo
2020-05-02

Abstract

Background: Accumulation of misfolded proteins is a common hallmark of several neurodegenerative disorders (NDs) which results from a failure or an impairment of the proteinquality 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: 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: 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: BBR and its analogues induce the clearance of misfolded proteins responsible for NDs, representing potential therapeutic tools to counteract these fatal disorders.
misfolding; neurodegeneration; spinal and bulbar muscular atrophy; protein aggregation; berberine; amyotrophic lateral sclerosis; frontotemporal dementia; autophagy; proteasome
Settore BIO/13 - Biologia Applicata
Settore BIO/09 - Fisiologia
Motor neuron degeneration in Spinal and Bulbar Muscular Atrophy: molecular approaches to counteract mutant androgen receptor neurotoxicity
Alternative translation initiation as a novel strategy to block toxicity of the mutant Androgen Receptor in SBMA
Selective translation of androgen receptor isoform A to prevent polyQ mediated toxicity in Kennedy’s disease
RAN translation of normal and expanded nucleotide repeat containing transcripts to neurotoxic polypetides in neurodegenerative diseases
Extracellular vescicles in the pathogenesis of frontotemporal dementia
Ruolo protettivo della proteina HSPB8 nelle malattie del motoneurone
Upregulation of HSPB8 as potential therapeutic approach in familial and sporadic ALS
Selective autophagic response to proteotoxicity in motorneurons and muscle of motor neuron diseases
Translating molecular mechanisms into ALS risk and patient's well-being
Stress granules and proteostasis in motor neurons: towards a mechanistic understanding of ALS (CureALS)
Membrane-less organelle pathology in ALS: identification of causes and rescuing factors (MLOMALS)
Colchicine for Amyotrophic Lateral Sclerosis: a phase II, randomized, double blind, placebo controlled, multicenter clinical trial (Co-ALS)
From RNA to Protein toxicity in motorneuron diseases
RAN translation of normal and expanded nucleotide repeat containing transcripts to neurotoxic polypetides in neurodegenerative diseases
Targeting RAN translation in ALS (Target-RAN)
The interplay between the “rna/protein quality control system” and “exosomes” as a spreading mechanism in amyotrophic lateral sclerosis (EX_ALS)
Extracellular vescicles in the pathogenesis of frontotemporal dementia
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Centro Interdipartimentale di Eccellenza per le Malattie Neurodegenerative CEND
Article (author)
File in questo prodotto:
File Dimensione Formato  
ijms-21-03443.pdf

accesso aperto

717.71 kB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/734791
Citazioni
  • ???jsp.display-item.citation.pmc??? 2
  • Scopus 2
  • ???jsp.display-item.citation.isi??? 2
social impact