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Sci Rep. 2017 Sep 12;7(1):11323. doi: 10.1038/s41598-017-11713-z.

Protein arginylation targets alpha synuclein, facilitates normal brain health, and prevents neurodegeneration.

Author information

1
University of Pennsylvania, School of Veterinary Medicine, Philadelphia, PA, 19104, USA.
2
The Scripps Research Institute, La Jolla, CA, 92037, USA.
3
University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, 19104, USA.
4
Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, USA.
5
University of Pennsylvania, School of Veterinary Medicine, Philadelphia, PA, 19104, USA. akashina@upenn.edu.

Abstract

Alpha synuclein (α-syn) is a central player in neurodegeneration, but the mechanisms triggering its pathology are not fully understood. Here we found that α-syn is a highly efficient substrate for arginyltransferase ATE1 and is arginylated in vivo by a novel mid-chain mechanism that targets the acidic side chains of E46 and E83. Lack of arginylation leads to increased α-syn aggregation and causes the formation of larger pathological aggregates in neurons, accompanied by impairments in its ability to be cleared via normal degradation pathways. In the mouse brain, lack of arginylation leads to an increase in α-syn's insoluble fraction, accompanied by behavioral changes characteristic for neurodegenerative pathology. Our data show that lack of arginylation in the brain leads to neurodegeneration, and suggests that α-syn arginylation can be a previously unknown factor that facilitates normal α-syn folding and function in vivo.

PMID:
28900170
PMCID:
PMC5595787
DOI:
10.1038/s41598-017-11713-z
[Indexed for MEDLINE]
Free PMC Article

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