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EnglishMacroautophagy/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 prodegradative 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.
Trehalose induces autophagy via lysosomal-mediated TFEB activation in models of motoneuron degeneration / P. Rusmini, K. Cortese, V. Crippa, R. Cristofani, M.E. Cicardi, V. Ferrari, G. Vezzoli, B. Tedesco, M. Meroni, E. Messi, M. Piccolella, M. Galbiati, M. Garrè, E. Morelli, T. Vaccari, A. Poletti. - In: AUTOPHAGY. - ISSN 1554-8627. - (2018 Nov 05). [Epub ahead of print]
| Titolo: | Trehalose induces autophagy via lysosomal-mediated TFEB activation in models of motoneuron degeneration |
| Autori: | RUSMINI, PAOLA (Primo) CORTESE, KATIA (Secondo) VACCARI, THOMAS (Penultimo) POLETTI, ANGELO (Ultimo) (Corresponding) |
| Parole Chiave: | amyotrophic lateral sclerosis; autophagy; calcineurin; galectin-3; lactulose; lysosomes; melibiose; motoneuron diseases; neurodegeneration; protein quality control; spinal and bulbar muscular atrophy; TFEB; trehalose |
| Settore Scientifico Disciplinare: | Settore BIO/13 - Biologia Applicata Settore BIO/09 - Fisiologia |
| Progetto: | Motor neuron degeneration in Spinal and Bulbar Muscular Atrophy: molecular approaches to counteract mutant androgen receptor neurotoxicity RAN translation of normal and expanded nucleotide repeat containing transcripts to neurotoxic polypetides in neurodegenerative diseases Extracellular vescicles in the pathogenesis of frontotemporal dementia Upregulation of HSPB8 as potential therapeutic approach in familial and sporadic ALS Stress granules and proteostasis in motor neurons: towards a mechanistic understanding of ALS (CureALS) Translating molecular mechanisms into ALS risk and patient's well-being From RNA to Protein toxicity in motorneuron diseases |
| Data di pubblicazione: | 5-nov-2018 |
| Rivista: | |
| Centro di ricerca: | Centro Interdipartimentale di Eccellenza per le Malattie Neurodegenerative CEND Centro Interuniversitario di Ricerca sulle Basi Molecolari delle Malattie Neurodegenerative |
| Tipologia: | Article (author) |
| Data ahead of print / Data di stampa: | 5-nov-2018 |
| Digital Object Identifier (DOI): | http://dx.doi.org/10.1080/15548627.2018.1535292 |
| Appare nelle tipologie: | 01 - Articolo su periodico |
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