title: Quercetin targets cysteine string protein (CSPalpha) and impairs synaptic transmission.
abstract: BACKGROUND
  Cysteine string protein (CSPalpha) is a synaptic vesicle protein that displays unique anti-neurodegenerative properties. CSPalpha is a member of the conserved J protein family, also called the Hsp40 (heat shock protein of 40 kDa) protein family, whose importance in protein folding has been recognized for many years. Deletion of the CSPalpha in mice results in knockout mice that are normal for the first 2-3 weeks of life followed by an unexplained presynaptic neurodegeneration and premature death. How CSPalpha prevents neurodegeneration is currently not known. As a neuroprotective synaptic vesicle protein, CSPalpha represents a promising therapeutic target for the prevention of neurodegenerative disorders.
  
  
  RESULTS
  Here, we demonstrate that the flavonoid quercetin promotes formation of stable CSPalpha-CSPalpha dimers and that quercetin-induced dimerization is dependent on the unique cysteine string region. Furthermore, in primary cultures of Lymnaea neurons, quercetin induction of CSPalpha dimers correlates with an inhibition of synapse formation and synaptic transmission suggesting that quercetin interfers with CSPalpha function. Quercetin's action on CSPalpha is concentration dependent and does not promote dimerization of other synaptic proteins or other J protein family members and reduces the assembly of CSPalpha:Hsc70 units (70kDa heat shock cognate protein).
  
  
  CONCLUSIONS
  Quercetin is a plant derived flavonoid and popular nutritional supplement proposed to prevent memory loss and altitude sickness among other ailments, although its precise mechanism(s) of action has been unclear. In view of the therapeutic promise of upregulation of CSPalpha and the undesired consequences of CSPalpha dysfunction, our data establish an essential proof of principle that pharmaceutical agents can selectively target the neuroprotective J protein CSPalpha.
authors.affiliation: Department of Anatomy and Cell Biology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Fenglian
authors.initials: F
authors.lastname: Xu
authors.forename: Juliane
authors.initials: J
authors.lastname: Proft
authors.forename: Sarah
authors.initials: S
authors.lastname: Gibbs
authors.forename: Bob
authors.initials: B
authors.lastname: Winkfein
authors.forename: Jadah N
authors.initials: JN
authors.lastname: Johnson
authors.forename: Naweed
authors.initials: N
authors.lastname: Syed
authors.forename: Janice E A
authors.initials: JE
authors.lastname: Braun
mesh_terms: D000818:Animals; D019281:Dimerization; D050956:HSP40 Heat-Shock Proteins / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D008565:Membrane Proteins / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D011794:Quercetin / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D050956:HSP40 Heat-Shock Proteins; D008565:Membrane Proteins; C088460:cysteine string protein; D011794:Quercetin