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.
Highlights
Journal Pre-proof these oligomers or fibrils in the brains of neurodegenerative disease patients, as the ubiquitin proteasome system (UPS) is incapable of degrading such large protein aggregates (1)(2)
A subset of autophagy inducers identified using the Dendra2-LC3 assay were tested for potential neuroprotective effects in cultured neurons expressing different ALS- or ALS/FTD-related proteins
Induction of autophagy in such cases likely leads to a toxic accumulation of autophagosomes that cannot be eliminated by fusion with lysosomes in neurons expressing mutant UBQLN2 or carrying the C9ORF72 mutation
Summary
Journal Pre-proof these oligomers or fibrils in the brains of neurodegenerative disease patients, as the UPS is incapable of degrading such large protein aggregates (1)(2). Mutations in several genes associated with different stages of the autophagy pathway have been identified as risk factors for the development of familial neurodegenerative diseases. Autophagic dysfunction is likely a factor in idiopathic neurodegenerative diseases, where the presence of protein aggregates impairs autophagic degradation in the absence of any underlying mutations (4).
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