| First Author | Brower CS | Year | 2013 |
| Journal | Mol Cell | Volume | 50 |
| Issue | 2 | Pages | 161-71 |
| PubMed ID | 23499006 | Mgi Jnum | J:198127 |
| Mgi Id | MGI:5495571 | Doi | 10.1016/j.molcel.2013.02.009 |
| Citation | Brower CS, et al. (2013) Neurodegeneration-associated protein fragments as short-lived substrates of the N-end rule pathway. Mol Cell 50(2):161-71 |
| abstractText | Protein 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 alpha-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 Abeta42, 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, alpha-synuclein, and APP can be selectively destroyed by the Arg/N-end rule pathway suggests that this pathway counteracts neurodegeneration. |
