No abstract

(Macro)autophagy is a bulk degradation process that mediates the clearance of long-lived proteins and organelles. Autophagy is initiated by double-membraned structures, which engulf portions of cytoplasm. The resulting autophagosomes ultimately fuse with lysosomes, where their contents are degraded. Although the term autophagy was first used in 1963, the field has witnessed dramatic growth in the last 5 years, partly as a consequence of the discovery of key components of its cellular machinery. In this review we focus on mammalian autophagy, and we give an overview of the understanding of its machinery and the signaling cascades that regulate it. As recent studies have also shown that autophagy is critical in a range of normal human physiological processes, and defective autophagy is associated with diverse diseases, including neurodegeneration, lysosomal storage diseases, cancers, and Crohn's disease, we discuss the roles of autophagy in health and disease, while trying to critically evaluate if the coincidence between autophagy and these conditions is causal or an epiphenomenon. Finally, we consider the possibility of autophagy upregulation as a therapeutic approach for various conditions.

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 ␣-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.Trehalose is a non-reducing disaccharide found in many organisms, including bacteria, yeast, fungi, insects, invertebrates, and plants. It is the natural hemolymph sugar of invertebrates. It functions to protect the integrity of cells against various environmental stresses like heat, cold, desiccation, dehydration, and oxidation by preventing protein denaturation (1). Many of the stress-protecting properties of trehalose were discovered in yeast (2); however, it also has beneficial effects in mammals where it is not endogenously synthesized. For instance, it may be a valuable tool for cryopreservation of cells (1, 3). It is not clear how trehalose mediates many of its protective effects, but some may be via its ability to act as chemical chaperone and influence protein folding through direct protein-trehalose interactions (4). Trehalose inhibits amyloid formation of insulin in vitro (5) and prevents aggregation of ␤-amyloid associated with Alzheimer disease (6). Recently, trehalose was shown to inhibit polyglutamine (polyQ) 3 -mediated protein aggregation in vitro, reduce mutant huntingtin aggregates and toxicity in cell models and alleviate polyQ-induced pathology in the R6/2 mouse model of Huntington disease (HD) (7). This protective effect was suggested to be caused by trehalose binding to expanded polyQ and stabilizing the partially unfolded mutant protein.HD is an autosomal-dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion, which results in an abnormally long polyQ tract in the N terminus of the huntingtin protein. Asymptomatic individuals have 35 or fewer CAG repeats, whereas HD is caused by 36 or more repeats. HD and related polyQ expansion diseases are associated with the formation of intraneuronal inclusions (also known as aggregates) by the mutant proteins containing the expanded polyQ tracts. The toxicity of mutant huntingtin is thought to be exposed...