Open AccessPhosphorylated NUB1 distinguishes α‐synuclein in Lewy bodies from that in glial cytoplasmic inclusions in multiple system atrophy
Author(s) -
Tanji Kunikazu,
Miki Yasuo,
Mori Fumiaki,
Kon Tomoya,
Kakita Akiyoshi,
Takahashi Hitoshi,
Wakabayashi Koichi
Publication year - 2019
Publication title -
brain pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.986
H-Index - 132
eISSN - 1750-3639
pISSN - 1015-6305
DOI - 10.1111/bpa.12728
Subject(s) - phosphorylation , dementia with lewy bodies , nedd8 , signal transducing adaptor protein , cytoplasm , microbiology and biotechnology , cytoplasmic inclusion , ubiquitin , atrophy , biology , lewy body , chemistry , parkinson's disease , pathology , biochemistry , dementia , medicine , disease , ubiquitin ligase , genetics , gene
Abstract Posttranslational modifications by phosphorylation, ubiquitination, neddylation and other pathways have emerged as major regulators of cellular functions. NEDD8 ultimate buster 1, NUB1, is an adaptor protein, which negatively regulates the levels of the ubiquitin‐like protein NEDD8 as well as neddylated proteins through proteasomal degradation. We previously reported that NUB1 is highly involved in the pathogenesis of synucleinopathy including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). In general, since phosphorylation is strongly related to the alteration of protein propensity, we examined if the fundamental function of NUB1 can be modulated by its phosphorylation. We created a series of phosphomimic mutants of NUB1. Among them, we found that phosphorylation of NUB1 at S46 (P‐NUB46) efficiently degrades aggregates using a cell‐based assay. Immunohistochemical studies have shown that specific antibodies against P‐NUB46 reacted with Lewy bodies in PD and DLB but not with glial cytoplasmic inclusions in MSA. Moreover, P‐NUB46 levels were significantly higher in the brains of patients with DLB than in control brains, and P‐NUB46 was extracted in an insoluble fraction of DLB. These findings suggest that the phosphorylation of NUB1 is modulated during the pathological process of Lewy body disease.