Trehalose induces autophagy via lysosomal-mediated TFEB activation in models of motoneuron degeneration

Abstract

Macroautophagy/autophagy, a defense mechanism against aberrant stresses, in neurons counteracts aggregate-prone misfolded protein toxicity. Autophagy induction might be beneficial in neurodegenerative diseases (NDs). The natural compound trehalose promotes autophagy via TFEB (transcription factor EB), ameliorating disease phenotype in multiple ND models, but its mechanism is still obscure. We demonstrated that trehalose regulates autophagy by inducing rapid and transient lysosomal enlargement and membrane permeabilization (LMP). This effect correlated with the calcium-dependent phosphatase PPP3/calcineurin activation, TFEB dephosphorylation and nuclear translocation. Trehalose upregulated genes for the TFEB target and regulator Ppargc1a, lysosomal hydrolases and membrane proteins (Ctsb, Gla, Lamp2a, Mcoln1, Tpp1) and several autophagy-related components (Becn1, Atg10, Atg12, Sqstm1/p62, Map1lc3b, Hspb8 and Bag3) mostly in a PPP3-and TFEB-dependent manner. TFEB silencing counteracted the trehalose pro-degradative activity on misfolded protein causative of motoneuron diseases. Similar effects were exerted by trehalase-resistant trehalose analogs, melibiose and lactulose. Thus, limited lysosomal damage might induce autophagy, perhaps as a compensatory mechanism, a process that is beneficial to counteract neurodegeneration.

Duplication and diversification of trehalase confers evolutionary advantages on lepidopteran insects

“…This finding suggests that Treh1b maintains cellular homeostasis through trehalose hydrolysis and plays important physiological roles in lysosomes. Consistent with this observation, recent studies have demonstrated trehalose-regulated autophagy through a mechanism related to changes in lysosomes (Rusmini & Cortese, 2018). Our data suggest that selectively driven subcellular adaptation played an important role in the functional diversification of duplicate Treh gene.…”

Targeting Aggrephagy for the Treatment of Alzheimer’s Disease

“…The natural disaccharide trehalose enhances TFEB nuclear translocation by inducing limited lysosomal membrane enlargement. It activates protein phosphatase-3 CB (PP3CB), calcineurin, and translocates TFEB into the nucleus, independent of inhibiting mTOR activity [169][170][171][172][173][174]. Trehalose treatment enhances the plaque clearance in APP/PS1 mice, and it reduces the tangle formation in P301S mice, again, independent of mTOR [170,171,173].…”

The Vicious Cycle Between α‐Synuclein Aggregation and Autophagic‐Lysosomal Dysfunction

“…Several compounds activating the autophagic cascade have been shown to reduce α‐syn toxicity in cellular and animal models . Interesting results have been obtained by using trehalose, a disaccharide able to activate autophagy processes and regulate the activity of TFEB, the main transcriptional regulator of the coordinated lysosomal expression and regulation network . The therapeutic effects of trehalose have been demonstrated in several in vitro and in vivo models of PD and other neurodegenerative diseases .…”

“…129 Interesting results have been obtained by using trehalose, a disaccharide able to activate autophagy processes [130][131][132] and regulate the activity of TFEB, the main transcriptional regulator of the coordinated lysosomal expression and regulation network. 133,134 The therapeutic effects of trehalose have been demonstrated in several in vitro and in vivo models of PD and other neurodegenerative diseases. 110,133,[135][136][137][138][139][140] Hoffman and colleagues showed that exposure of H4 cells and primary neurons to trehalose, before α-syn exposure, prevents lysosomal enlargement and formation of massive α-syn aggregates.…”