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.
Highlights
Alpha synuclein (α –syn) is a central player in neurodegeneration
Protein arginylation is a posttranlsational modification mediated by arginyltransferase ATE1 that transfers Arg from tRNA directly to protein targets[4]
It has been previously believed that ATE1 targets exclusively the N-terminus of proteolytically generated Asp and Glu, but recent studies showed that the acidic side chains of Asp and Glu can serve as targets for arginylation in intact proteins[16]
Summary
Our study demonstrates for the first time that α-syn can be arginylated in vivo through a novel mid-chain mechanism that can target intact proteins in vivo. Our results suggest that arginylation is a previously unknown mechanism that maintains normal intracellular levels of α-syn and facilitates normal brain health. This finding introduces a new level of regulation into the studies of α-syn and potentially yields a new target pathway that could lead to prevention and treatment of neurodegeneration. Regardless of the exact mechanism, it appears likely that arginylation constitutes a previously unknown core neuroprotective mechanism that facilitates the seeding of normal α-syn conformation in cells This hypothesis will be elucidated in further studies. High throughput studies from other groups show that ATE1 is significantly reduced in dopaminergic neurons of human PD patients (Fig. 9), suggesting that this reduction likely correlates with reduced α-syn arginylation and neurodegeneration. P-values were determined by one-tailed Welch’s t-test and one-tailed and two-tailed paired Student’s t-test
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