title: Neurodegeneration-associated protein fragments as short-lived substrates of the N-end rule pathway.
abstract: 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 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.
authors.affiliation: Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Brower
authors.forename: Konstantin I
authors.initials: KI
authors.lastname: Piatkov
authors.forename: Alexander
authors.initials: A
authors.lastname: Varshavsky
mesh_terms: D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D002457:Cell Extracts; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D057174:Frontotemporal Lobar Degeneration / Q000378:metabolism*; D057809:HEK293 Cells; D006207:Half-Life; D006801:Humans; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D019636:Neurodegenerative Diseases / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D055550:Protein Stability; D059748:Proteolysis; D012156:Reticulocytes / Q000378:metabolism; D012441:Saccharomyces cerevisiae; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D002457:Cell Extracts; D004268:DNA-Binding Proteins; D010446:Peptide Fragments; D051844:alpha-Synuclein; D016875:tau Proteins; D001120:Arginine; D002154:Calpain; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3