Sarkar, S., Ravikumar, B., Floto, R.A. & Rubinsztein, D.C. Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies. Cell Death. Differentiation. 16, 46-56

Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
Cell death and differentiation (Impact Factor: 8.18). 01/2009; 16(1):46-56. DOI: 10.1038/cdd.2008.110
Source: PubMed


The formation of intra-neuronal mutant protein aggregates is a characteristic of several human neurodegenerative disorders, like Alzheimer's disease, Parkinson's disease (PD) and polyglutamine disorders, including Huntington's disease (HD). Autophagy is a major clearance pathway for the removal of mutant huntingtin associated with HD, and many other disease-causing, cytoplasmic, aggregate-prone proteins. Autophagy is negatively regulated by the mammalian target of rapamycin (mTOR) and can be induced in all mammalian cell types by the mTOR inhibitor rapamycin. It can also be induced by a recently described cyclical mTOR-independent pathway, which has multiple drug targets, involving links between Ca(2+)-calpain-G(salpha) and cAMP-Epac-PLC-epsilon-IP(3) signalling. Both pathways enhance the clearance of mutant huntingtin fragments and attenuate polyglutamine toxicity in cell and animal models. The protective effects of rapamycin in vivo are autophagy-dependent. In Drosophila models of various diseases, the benefits of rapamycin are lost when the expression of different autophagy genes is reduced, implicating that its effects are not mediated by autophagy-independent processes (like mild translation suppression). Also, the mTOR-independent autophagy enhancers have no effects on mutant protein clearance in autophagy-deficient cells. In this review, we describe various drugs and pathways inducing autophagy, which may be potential therapeutic approaches for HD and related conditions.

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    • "Furthermore, daily postligation treatments of the mTOR inhibitor rapamycin delayed ligation-induced salivary gland atrophy in mice (Bozorgi et al. 2014). However, rapamycin is also a potent inducer of autophagy (Sarkar et al. 2009). It is unclear what effect rapamycin has on autophagy signaling in this duct ligation model. "
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    ABSTRACT: Autophagy is a catabolic process that has been shown to have a role in many cellular processes including the removal of excessive or damaged proteins and protein aggregates. The salivary glands play a critical role in oral health, and their secretory capacity may be critically intertwined with the autophagic process. This review describes the role of autophagy activation in normal salivary gland homeostasis and during the glandular stress responses of therapeutic radiation, ductal ligation, autoimmunity, and salivary gland adenoid cystic carcinoma. © International & American Associations for Dental Research 2015.
    Journal of dental research 06/2015; 94(8). DOI:10.1177/0022034515590796 · 4.14 Impact Factor
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    • "Enhancement of macroautophagy has been suggested to be a rational approach for treating diseases characterized by the accumulation of aggregation-prone proteins [4]. Upregulation of autophagy can be achieved by inhibition of the mammalian target of rapamycin (mTOR) or by mTOR independent pathways [5]. mTOR inhibition exerts neuroprotective effects in several models of neurodegenerative diseases [6], e.g., in models for polyglutamine diseases expressing a huntingtin fragment [7] or a mutant ataxin-3 protein [8]. "
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    ABSTRACT: Neurofibrillary tangles are intracellular inclusions made of tau protein that accumulates in neurons in Alzheimer's disease (AD) and in other tauopathies. We have investigated the ability of the rapamycin ester CCI-779/Temsilorimus, a mTOR inhibitor with better stability and pharmacological properties compared to rapamycin, to interfere with the development of a motor phenotype and tau pathology in a mutant tau mouse model developing neurofibrillary tangles, by stimulation of mTOR dependent macroautophagy. Mutant tau mice (Tg30) were treated with CCI-779 before onset of motor signs for 7 months (from 5 to 12 months of age) or after the onset of motor signs for 2 months (from 10 to 12 months of age). End-point motor deficits were 50% lower in the group of Tg30 mice treated for 7 months. Inhibition of mTOR signaling and stimulation of macroautophagy in the brain of CCI-779 treated Tg30 mice was suggested by decreased phosphorylation of mTOR downstream signaling molecules p70S6 kinase and Akt and increased level of the autophagy markers Rab7 and LC3-II. CCI-779 treatment decreased the brain levels of Sarkosyl-insoluble tau and phosphotau inTg30 mice both after 2 months or 7 months of treatment. The density of neurofibrillary tangles was significantly decreased when treatment was started prior onset of motor signs. These results indicate that stimulation of mTOR dependent autophagy by CCI-779 compound is efficient to counteract the accumulation of abnormal tau when administered early or late in a tauopathy model and to improve a motor deficit when started before onset of motor signs.
    Journal of Alzheimer's disease: JAD 11/2014; 44(4). DOI:10.3233/JAD-142097 · 4.15 Impact Factor
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    • "Finally, upregulating autophagy can ameliorate symptoms and pathology in many HD models. Inducing mammalian target of rapamycin (mTOR)-dependent autophagy reduced neurodegeneration in a fly HD model and improved behavior and motor performance in mouse HD models (Ravikumar et al., 2004; Berger et al., 2006; Sarkar et al., 2009). Inducing autophagy independently of mTOR also reduced mHtt aggregation and toxicity in various models (Sarkar et al., 2005; Ma et al., 2007; Zhang et al., 2007; Williams et al., 2008; Rose et al., 2010; Tsvetkov et al., 2010). "
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    ABSTRACT: Selective neuronal loss is a hallmark of neurodegenerative diseases, including Huntington's disease (HD). Although mutant huntingtin, the protein responsible for HD, is expressed ubiquitously, a subpopulation of neurons in the striatum is the first to succumb. In this review, we examine evidence that protein quality control pathways, including the ubiquitin proteasome system, autophagy, and chaperones, are significantly altered in striatal neurons. These alterations may increase the susceptibility of striatal neurons to mutant huntingtin-mediated toxicity. This novel view of HD pathogenesis has profound therapeutic implications: protein homeostasis pathways in the striatum may be valuable targets for treating HD and other misfolded protein disorders.
    Frontiers in Cellular Neuroscience 08/2014; 8:218. DOI:10.3389/fncel.2014.00218 · 4.29 Impact Factor
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