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

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.

Arginyltransferase knockdown attenuates cardiac hypertrophy and fibrosis through TAK1-JNK1/2 pathway

“…Having an insight into the mechanisms and potential targets implicit in cardiac hypertrophy will provide novel methodologies for the prevention or treatment of cardiovascular disease. Arginyltransferase (ATE1) is an evolutionary conserved enzyme and has a crucial role in multiple biological events [15][16][17] . The physiological importance of ATE1 in higher eukaryotes has been shown in previous studies where in case of Mus musculus, ATE1 deletion contributes to embryonic lethality due to abnormal cardiac morphogenesis and impaired angiogenesis 18 .…”

Amino Assets: How Amino Acids Support Immunity

“…Amino acid-derived PTMs have been investigated in bacteria, including lysinylation (Kristian et al, 2003) and alanylation (Saar-Dover et al, 2012), while arginylation prevents neurodegeneration in mice (Wang et al, 2017a). However, many PTMs have not been investigated in an immune cell, or even a mammalian, context.…”

The N Termini of TAR DNA-Binding Protein 43 (TDP43) C-Terminal Fragments Influence Degradation, Aggregation Propensity, and Morphology

“…N-terminal Asn, Gln, Asp, Glu, and Cys are also destabilizing but require enzymatic modifications, including deamidation of Asn and Gln by Ntan1 and Ntaq1, respectively ( 59 , 60 ), and N-terminal arginylation of Asp, Glu, or oxidized Cys by the Ate1 -encoded arginyl-transferase (arginyl-tRNA protein transferase 1 [ATE1]) ( 61 – 63 ). ATE1-dependent posttranslational arginylation of proteins is emerging as an important player in maintaining nervous system function and in preventing neurodegeneration ( 64 – 68 ).…”