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 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: 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.
Highlights
Protein homeostasis ensures proteome integrity and its proper regulation is essential for cell health and survival
To analyze the intracellular kinetics of wtAR and androgen receptor (AR) polyQ in NSC34 cell line, we used a chimeric protein coding for Green Fluorescent Protein (GFP) fused with wt AR (GFP-AR.Q22) or ARpolyQ (GFP-AR.Q48)
We initially assessed the specificity of the antibody both in Western Blot (WB) analysis and filter retardation assay (FRA) by using NSC34 cells expressing the exogenous recombinant AR with an elongated tract of 46 glutamines (AR.Q46) compared to a mock-transfected sample used as negative control
Summary
Protein homeostasis (proteostasis) ensures proteome integrity and its proper regulation is essential for cell health and survival. The mechanism of protein misfolding found in SBMA has been related to HD and other polyQ diseases, since they share the same type of mutation found in ARpolyQ even if present in other different proteins. NAXs were selected from a proprietary class of BBR semisynthetic structural analogues [U.S Pat. 8188,109B2 to Naxospharma s.r.l.], characterized by the presence of (hetero)aromatic moieties, bonded to the 13-position of the parent alkaloid skeleton through a linker of variable length, in order to enhance the propensity for additional noncovalent aromatic interactions on the cellular target site(s) [69,70,71,72,73,74] This could result in different biophysical effects with respect to the parent BBR and, hopefully, in a better biological outcome
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