Quercetin Targets Cysteine String Protein

Cysteine string protein (CSP[alpha]) is a synaptic vesicle protein that displays unique anti-neurodegenerative properties. CSP[alpha] 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 CSP[alpha] 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 CSP[alpha] prevents neurodegeneration is currently not known. As a neuroprotective synaptic vesicle protein, CSP[alpha] represents a promising therapeutic target for the prevention of neurodegenerative disorders. Here, we demonstrate that the flavonoid quercetin promotes formation of stable CSP[alpha]-CSP[alpha] dimers and that quercetin-induced dimerization is dependent on the unique cysteine string region. Furthermore, in primary cultures of Lymnaea neurons, quercetin induction of CSP[alpha] dimers correlates with an inhibition of synapse formation and synaptic transmission suggesting that quercetin interfers with CSP[alpha] function. Quercetin's action on CSP[alpha] is concentration dependent and does not promote dimerization of other synaptic proteins or other J protein family members and reduces the assembly of CSP[alpha]:Hsc70 units (70kDa heat shock cognate protein). 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 CSP[alpha] and the undesired consequences of CSP[alpha] dysfunction, our data establish an essential proof of principle that pharmaceutical agents can selectively target the neuroprotective J protein CSP[alpha].