کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1996341 | 1065460 | 2013 | 11 صفحه PDF | دانلود رایگان |
SummaryProtein aggregates are a common feature of neurodegenerative syndromes. Specific protein fragments were found to be aggregated in disorders including Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease. Here, we show that the natural C-terminal fragments of Tau, TDP43, and α-synuclein are short-lived substrates of the Arg/N-end rule pathway, a processive proteolytic system that targets proteins bearing “destabilizing” N-terminal residues. Furthermore, a natural TDP43 fragment is shown to be metabolically stabilized in Ate1−/− fibroblasts that lack the arginylation branch of the Arg/N-end rule pathway, leading to accumulation and aggregation of this fragment. We also found that a fraction of Aβ42, the Alzheimer’s disease-associated fragment of APP, is N-terminally arginylated in the brains of 5xFAD mice and is degraded by the Arg/N-end rule pathway. The discovery that neurodegeneration-associated natural fragments of TDP43, Tau, α-synuclein, and APP can be selectively destroyed by the Arg/N-end rule pathway suggests that this pathway counteracts neurodegeneration.
► Neurodegeneration-associated fragments bear destabilizing N-terminal residues
► Destabilizing activity of these N-terminal residues is conserved in evolution
► Neurodegeneration-associated fragments are Arg/N-end rule substrates
► The Arg/N-end rule pathway may be a repressor of neurodegeneration
Journal: - Volume 50, Issue 2, 25 April 2013, Pages 161–171