Trehalose, a Novel mTOR-independent Autophagy Enhancer, Accelerates the Clearance of Mutant Huntingtin and α-Synuclein*

By Sovan Sarkar, J. Davies, Zebo Huang, A. Tunnacliffe, D. Rubinsztein. Journal of Biological Chemistry, 2007

1,069 citations recorded by the source corpus.

Trehalose, a disaccharide present in many non-mammalian species, protects cells against various environmental stresses. Whereas some of the protective effects may be explained by its chemical chaperone properties, its actions are largely unknown. Here we report a novel function of trehalose as an mTOR-independent autophagy activator. Trehalose-induced autophagy enhanced the clearance of autophagy substrates like mutant huntingtin and the A30P and A53T mutants of α-synuclein, associated with Huntington disease (HD) and Parkinson disease (PD), respectively. Furthermore, trehalose and mTOR inhibition by rapamycin together exerted an additive effect on the clearance of these aggregate-prone proteins because of increased autophagic activity. By inducing autophagy, we showed that trehalose also protects cells against subsequent pro-apoptotic insults via the mitochondrial pathway. The dual protective properties of trehalose (as an inducer of autophagy and chemical chaperone) and the combinatorial strategy with rapamycin may be relevant to the treatment of HD and related diseases, where the mutant proteins are autophagy substrates.

Subfields: Cellular and Molecular Neuroscience, Epidemiology, Neurology

View Paper: https://www.semanticscholar.org/paper/0f2c2d16534b45d1a612986a2cf414db4d8ffd52

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

In Epidemiology

In Neurology

Citations in the corpus

Autophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities. (2017, positive): “Rapamycin and its analogues have shown benefits as autophagy inducers in animal models of AD, PD, FTD, HD and PrP (Cortes et al., 2012; Jiang et al., 2014; Menzies et al., 2010; Ozcelik et al., 2013; Ravikumar et al., 2004; Sarkar et al., 2008; Spilman et al., 2010; Wang et al., 2013b).”
Guidelines for the use and interpretation of assays for monitoring autophagy (2012, background): “Trehalose An inducer of autophagy that may be relevant for the treatment of different neurodegenerative diseases.(253,254)”
Molecular mechanisms and potential therapeutical targets in Huntington's disease. (2010, background): “At the same line, trehalose has been found to induce autophagy of mutant huntingtin and protect cells against subsequent pro-apoptotic insults via the mitochondrial pathway (499).”
Pathogenic Lysosomal Depletion in Parkinson's Disease (2010, background): “Trehalose, a disaccharide homologous to sucrose, has been recently reported to accelerate the clearance of mutant huntingtin and -synuclein and to protect cultured neurons against mitochondria-dependent apoptotic insults by inducing autophagy (Sarkar et al., 2007).”
Autophagy and apoptosis dysfunction in neurodegenerative disorders. (2014, neutral): “…of HD (Koga et al., 2011) CMA degrades mutated Htt (Bauer et al., 2010) CMA is up regulated in early stage of HD (Koga et al., 2011) Trehalose (Sarkar et al., 2007) Rapamycin (Mendelsohn and Larrick, 2011; Ravikumar et al., 2002) Rilmenidine (Rose et al., 2010) Amyotrophic lateral sclerosis…”
FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. (2007, background): “Thus, most of Akt’s effects on lysosomal proteolysis must be through an mTOR-independent mechanism, as has been suggested previously (Sarkar et al., 2007; Tassa et al., 2003; Yamamoto et al., 2006).”
FoxO3 controls autophagy in skeletal muscle in vivo. (2007, background): “…be induced by mTOR-independent mechanisms: leucine starvation has been reported to induce mTOR-independent autophagy in cultured myotubes (Mordier et al., 2000), and mTOR has also been found to be dispensable in other cell systems (Kochl et al., 2006; Sarkar et al., 2007; Yamamoto et al., 2006).”
Autophagy in the Cellular Energetic Balance (2011, positive): “Other sugars, such as the disaccharide trehalose, physiologically present in many nonmammalian species, also induce macroautophagy and clearance of pathogenic proteins (Sarkar et al., 2007).”
Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (2012, neutral): “Trehalose An inducer of autophagy that may be relevant for the treatment of different neurodegenerative diseases.(1241,1518,1519) 41.”
Autophagy Inhibition Compromises Degradation of Ubiquitin-Proteasome Pathway Substrates (2009, positive): “We have previously demonstrated that autophagy-inducers can further increase LC3-II levels in bafilomycin A1-treated cells, indicating that such compounds increase autophagosome formation (Sarkar et al., 2007).”