{"doi":"10.1016/j.jbc.2021.101437","title":"Shining a light on autophagy in neurodegenerative diseases","abstract":"Small-molecule modulators of autophagy have been widely investigated as potential therapies for neurodegenerative diseases. In a recent issue of JBC, Safren et al. described a novel assay that uses a photoconvertible fusion protein to identify compounds that alter autophagic flux. Autophagy inducers identified using this assay were found to either alleviate or exacerbate neurotoxicity in different cellular models of amyotrophic lateral sclerosis, challenging the notion that autophagy stimulation can be used as a one-size-fits-all therapy for neurodegenerative disease. Small-molecule modulators of autophagy have been widely investigated as potential therapies for neurodegenerative diseases. In a recent issue of JBC, Safren et al. described a novel assay that uses a photoconvertible fusion protein to identify compounds that alter autophagic flux. Autophagy inducers identified using this assay were found to either alleviate or exacerbate neurotoxicity in different cellular models of amyotrophic lateral sclerosis, challenging the notion that autophagy stimulation can be used as a one-size-fits-all therapy for neurodegenerative disease. Development of a specific live-cell assay for native autophagic fluxJournal of Biological ChemistryVol. 297Issue 3PreviewAutophagy is an evolutionarily conserved pathway mediating the breakdown of cellular proteins and organelles. Emphasizing its pivotal nature, autophagy dysfunction contributes to many diseases; nevertheless, development of effective autophagy modulating drugs is hampered by fundamental deficiencies in available methods for measuring autophagic activity or flux. To overcome these limitations, we introduced the photoconvertible protein Dendra2 into the MAP1LC3B locus of human cells via CRISPR/Cas9 genome editing, enabling accurate and sensitive assessments of autophagy in living cells by optical pulse labeling. Full-Text PDF Open Access Cellular proteostasis is governed by a tight coordination between protein synthesis and protein elimination. The latter process involves protein degradation by either the ubiquitin proteasome system (UPS) or the autophagy-lysosome pathway (ALP), encompassing macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Multiple lines of evidence suggest that macroautophagy (referred to hereafter as “autophagy”) plays a key role in eliminating toxic protein aggregates frequently observed in neurodegenerative diseases, in turn implying that upregulation of autophagy could be neuroprotective. However, progress in identifying small molecules that induce autophagy has been limited by the drawbacks of existing assays designed to monitor “autophagic flux,” a term used to describe the entire dynamic process of autophagic degradation. Autophagy involves the encapsulation of cellular components (or “cargo”) into double-membraned structures named autophagosomes. Autophagosomes subsequently fuse with lysosomes, resulting in the degradation of the cargo by lysosomal enzymes. The initiation of autophagosome formation is regulated by numerous upstream signaling proteins, including the kinases mTOR and AMPK. The pathology of neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) involves an accumulation in the central nervous system (CNS) of fibrillar aggregates formed by one or more peptides or proteins, including amyloid-beta and tau in AD, alpha-synuclein in PD, and TDP-43 and FUS in ALS/FTD. Autophagy is thought to be primarily responsible for eliminating these oligomers or fibrils in the brains of neurodegenerative disease patients, as the UPS is incapable of degrading such large protein aggregates (1Kocaturk N.M. Gozuacik D. Crosstalk between mammalian autophagy and the ubiquitin-proteasome system.Front. Cell Dev. Biol. 2018; 6: 128Crossref PubMed Scopus (250) Google Scholar, 2Scotter E.L. Vance C. Nishimura A.L. Lee Y.B. Chen H.J. Urwin H. 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