Welcome to the new version of CaltechAUTHORS. Login is currently restricted to library staff. If you notice any issues, please email coda@library.caltech.edu
Published April 25, 2013 | Supplemental Material + Accepted Version
Journal Article Open

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.

Additional Information

© 2013 Elsevier Inc. Received: November 26, 2012; Revised: January 18, 2013; Accepted: February 6, 2013; Published: March 14, 2013. We thank E. Udartseva for genotyping mouse strains and C. Rosen for help with Ate1 isoforms. We are also grateful to members of the Varshavsky laboratory for their assistance and to S. Pease, J. Costanza, J. Mata, K. Flee, and J. Gutierrez for their help, advice, and support at the mouse transgenic facility. We thank the Harvard Brain Tissue Resource Center (which is supported in part by an NIH grant [R24-MH 068855]) for supplying human brain samples. This study was supported by grants to A.V. from the NIH (DK039520, GM031530, and GM085371).

Attached Files

Accepted Version - nihms445915.pdf

Supplemental Material - mmc1.pdf

Files

nihms445915.pdf
Files (7.4 MB)
Name Size Download all
md5:190e065780b6a60eabe90da881027597
4.2 MB Preview Download
md5:ab83add46f2e05161ce8535adffad5e1
3.2 MB Preview Download

Additional details

Created:
August 19, 2023
Modified:
October 23, 2023