期刊
JOURNAL OF NEUROCHEMISTRY
卷 154, 期 4, 页码 354-371出版社
WILEY
DOI: 10.1111/jnc.15002
关键词
autosis; chaperone; hypoxia-ischaemia; mitophagy; motor neuron; Parkinsonism
资金
- H2020 Research and Innovation Programme [01ED1601A]
- Fondazione ARiSLA [ALS-HSPB8]
- Innovative Medicines Initiative Joint Undertaking [115568]
- Italian Ministry of University and Research (MIUR) PRIN [2015LFPNMN, 2017F2A2C5]
- Vetenskapsradet
- Marta and Gunnar V. Philipson Foundation
- Fondazione Regionale per la Ricerca Biomedica [2015-0023]
- Michael J. Fox Foundation for Parkinson's Research [ID12095]
- Stockholm County Council
- Swedish Cancer Foundation
- Agenzia Italiana del Farmaco, Ministero della Salute
- Hjarnfonden
- Agence Nationale de la Recherche [ANR-10-IAIHU-06]
- Swedish Radiation Safety Authority
- Stiftelsen Frimurare Barnhuset i Stockholm
- National Health and Medical Research Council [APP1019833, APP1104295, APP509217]
- Barncancerfonden
- Seventh Framework Programme [2012-00034508, 201600066513]
- Fondation de France [2012-00034508 201600066513]
- Fondazione Telethon [GGP14039, GGP19128]
- Fondazione Cariplo [2014-0686]
- Fondazione AriSLA
- Association Francaise contre les Myopathies [AFM Telethon 16406]
- Swedish Research Council
- Region Stockholm
- Brain Foundation
- Horizon 2020
In autophagy long-lived proteins, protein aggregates or damaged organelles are engulfed by vesicles called autophagosomes prior to lysosomal degradation. Autophagy dysfunction is a hallmark of several neurodegenerative diseases in which misfolded proteins or dysfunctional mitochondria accumulate. Excessive autophagy can also exacerbate brain injury under certain conditions. In this review, we provide specific examples to illustrate the critical role played by autophagy in pathological conditions affecting the brain and discuss potential therapeutic implications. We show how a singular type of autophagy-dependent cell death termed autosis has attracted attention as a promising target for improving outcomes in perinatal asphyxia and hypoxic-ischaemic injury to the immature brain. We provide evidence that autophagy inhibition may be protective against radiotherapy-induced damage to the young brain. We describe a specialized form of macroautophagy of therapeutic relevance for motoneuron and neuromuscular diseases, known as chaperone-assisted selective autophagy, in which heat shock protein B8 is used to deliver aberrant proteins to autophagosomes. We summarize studies pinpointing mitophagy mediated by the serine/threonine kinase PINK1 and the ubiquitin-protein ligase Parkin as a mechanism potentially relevant to Parkinson's disease, despite debate over the physiological conditions in which it is activated in organisms. Finally, with the example of the autophagy-inducing agent rilmenidine and its discrepant effects in cell culture and mouse models of motor neuron disorders, we illustrate the importance of considering aspects such a disease stage and aggressiveness, type of insult and load of damaged or toxic cellular components, when choosing the appropriate drug, timepoint and duration of treatment.
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