Emerging evidence suggest a neuroprotective role of curcumin in Alzheimer's disease and several clinical trials have been initiated to examine the effect of curcumin in AD patients. Contrary to this, curcumin has been shown to increase the aggregation of mutant huntingtin and also enhance toxicity associated in PC12 cells by augmenting the proteasomal dysfunction 
. Impairment of proteasomal machinery is implicated in other amyloid disorders including AD and HD 
, therefore, if curcumin enhances a proteasomal defect, a similar increase in aggregation is expected on treatment for other amyloid proteins. Though Aβ peptide and mutant huntingtin protein form similar cross β-sheet structures, the major difference lies in their sequence. While Aβ lacks glutamine repeats, huntingtin protein is glutamine rich. This intrigued us and we investigated aggregation of mutant huntingtin with expanded glutamine repeats and Het-s, a non Q-rich fungal prion protein, after curcumin treatment in yeast. In accordance with a protective effect of curcumin for neurodegenerative disorders, we demonstrate an inhibitory effect of curcumin on both Q-rich and non Q-rich protein aggregation in yeast and describe the likely mechanisms of inhibition.
The molecular mechanism of action of curcumin is complex and multiple molecular targets have been proposed by several independent studies 
. Curcumin has been shown to have a therapeutic effect on AD by reducing oxidative damage 
, decreasing β-amyloid formation by inhibiting GSK-3β-mediated presenilin-1 levels 
and Wnt/β-catenin signaling pathway activation 
and also inhibiting trafficking and maturation of Amyloid Precursor Protein (APP) into Aβ peptide 
. We scored aggregation in eight homozygous deletion strains hypersensitive to curcumin and only deletion of VPS36
caused significant inhibition of formation of aggregates of mutant huntingtin. Vps36, a component of the ESCRT-II complex, appeared to be a functional target of curcumin as it was downregulated in a dose and time-dependent manner. Vps36 is involved in trafficking soluble and integral membrane proteins from the trans-golgi network to the perivacuolar region and finally to the vacuole 
. As misfolded proteins including mutant huntingtin are known to localize in the perivacuolar region 
, we propose that in vivo
deletion or downregulation of Vps36 caused by curcumin treatment prevents recruitment of misfolded protein to the perivacuolar compartment and thus inhibits formation of visible large aggregates. The importance of protein trafficking pathways in aggregation of amyloid proteins has been demonstrated previously. Several genes from endocytic pathway and vacuolar protein sorting are known to affect aggregation of amyloid proteins including mutant huntingtin 
and prion proteins 
. In compliance with previous work, our work further strengthens that protein trafficking pathways can be exploited for developing small molecule inhibitors of amyloid disorders.
Curcumin has been shown to destabilize Aβ fibrils but disassembly of mutant huntingtin by curcumin has not been described earlier. In vitro
, disruption or remodelling of mutant huntingtin aggregates pre-formed in yeast clearly supports anti-aggregation potential of curcumin. Furthermore, our findings are supported by a very recent report that shows a clear decrease in number of aggregates in the striatum of knock-in HD mouse model 
. Curcumin is known to cross the blood-brain barrier but bioavailibity is still poor. Hence, analogs of curcumin or combination of small molecules that increase the bioavailability of the active molecule need to be evaluated.
Morin, a polyphenol, present in red wine, has been suggested to have potential for developing therapies for AD and tauopathies by inhibiting GSK-3β 
. Recently, it has been reported to inhibit amyloid formation of Islet Amyloid Polypeptide (IAPP) 
. We show that morin is an effective inhibitor of mutant huntingtin aggregates. Morin treatment also led to slight inhibition of non-Q rich aggregates. Further work is required to understand the mechanism of action of morin.
The key findings of our study are that curcumin is a more potent inhibitor of both Q-rich and non Q-rich aggregates than morin and α-tocopherol. Furthermore, it inhibits mutant huntingtin aggregation by acting through protein trafficking pathways and also destabilizes pre-formed aggregates. Based on our data and previous studies, curcumin is a promising compound for development of preventives and therapeutics for both Q-rich and non Q-rich amyloid disorders.