期刊
AUTOPHAGY
卷 15, 期 4, 页码 631-651出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2018.1535292
关键词
Amyotrophic lateral sclerosis; autophagy; calcineurin; galectin-3; lactulose; lysosomes; melibiose; motoneuron diseases; neurodegeneration; protein quality control; spinal and bulbar muscular atrophy; TFEB; trehalose
类别
资金
- Fondazione Telethon, Italy [GGP14039, GGP13225]
- Fondazione Cariplo, Italy [2014-0686, 2017_0747]
- Fondazione AriSLA, Italy [ALS_HSPB8]
- Association Francaise contre les Myopathies, France [AFM Telethon] [16406]
- Associazione Italiana Ricerca sul Cancro [AIRC] [15954]
- Universita degli Studi di Milano
- Italian Ministry of Health [GR-2011-02347198]
- Associazione Italiana Ricerca sul Cancro (AIRC Fellowship)
- Fondazione Regionale per la Ricerca Biomedica (FRRB) [2015-0023]
- Italian Ministry of University and Research (MIUR) [2015LFPNMN]
- European Molecular Biology Organization (EMBO) [537 - 2015]
- International Brain Research Organization (IBRO)
- Italian Ministry of University and Research (MIUR) [Fondo per il Finanziamento delle Attivita Base di Ricerca (FFABR)]
- Agenzia Italiana del Farmaco (AIFA)
- EU Joint Programme -Neurodegenerative Disease Research (JPND) project
- European Union's Horizon 2020 research and innovation programme [643417, 01ED1601A]
- Italian Ministry of University and Research [Progetto Dipartimenti di Eccellenza]
- JPND
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.
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