2016
DOI: 10.2174/1871527314666150821101522
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Novel Lactulose and Melibiose Targeting Autophagy to Reduce PolyQ Aggregation in Cell Models of Spinocerebellar Ataxia 3

Abstract: Trehalose, a chemical chaperone and mTOR-independent autophagy enhancer, has shown promise in models of Huntington's disease, Parkinson's disease and tauopathies. In this study, two trehalase analogs, lactulose and melibiose, were examined for their potentials in spinocerebellar ataxia treatment. Using a SCA3 ATXN3/Q75-GFP cell model, we found that the ATXN3/Q75 aggregation was significantly prohibited by lactulose and melibiose because of their abilities to up-regulate autophagy. Meanwhile, lactulose and meli… Show more

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Cited by 27 publications
(32 citation statements)
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“…LC3 and p62 serve as the useful marker of autophagy induction and clearance of protein aggregates via autophagosome, respectively. Numerous studies using different interventions, such as far‐infrared radiation and chemical enhancers of autophagy, have consistently achieved a decrease of polyQ expression in SCA type 3 (SCA3) by increasing the LC3‐II concentration and decreasing P62 expression. Thus, autophagy induction could potentially be used as a therapeutic strategy for controlling the progression of SCA by ameliorating mutant‐protein‐induced neuron death .…”
Section: Discussionmentioning
confidence: 99%
“…LC3 and p62 serve as the useful marker of autophagy induction and clearance of protein aggregates via autophagosome, respectively. Numerous studies using different interventions, such as far‐infrared radiation and chemical enhancers of autophagy, have consistently achieved a decrease of polyQ expression in SCA type 3 (SCA3) by increasing the LC3‐II concentration and decreasing P62 expression. Thus, autophagy induction could potentially be used as a therapeutic strategy for controlling the progression of SCA by ameliorating mutant‐protein‐induced neuron death .…”
Section: Discussionmentioning
confidence: 99%
“…However, in these pathologies, autophagy fails to remove toxic molecules due to their abundance and to the inhibitory effects of long polyQ mutation on mechanism initiating autophagy [167]. Consistently, pharmacological treatments targeting autophagy provided beneficial effects in several models of hereditary cerebellar ataxia [168][169][170][171]. Moreover, positive outcomes associated with changes in autophagy were also induced by motor training administered at presymptomatic stages in the tambaleante (tbl) mouse model of ataxia [172].…”
Section: Cellular Mechanisms Underlying Functional Cerebellar Reservementioning
confidence: 94%
“…Trehalose, a compound already described in the above section as a chemical chaperone able to influence protein folding, is also an mTOR‐independent autophagy inducer that can enhance clearance of aggregation‐prone mutant HTT and ATXN3 and protect against apoptotic insults in cells via its autophagy‐inducing properties . The combinatory effects of its autophagy‐inducing and chemical chaperone activities, together with its lack of toxicity, places trehalose as a potentially interesting compound for polyQ disease therapy.…”
Section: Therapeutic Strategies For Polyq Diseasesmentioning
confidence: 95%