Autophagic adapter protein NBR1 is localized in Lewy bodies and glial cytoplasmic inclusions and is involved in aggregate formation in α-synucleinopathy

Abstract

Macroautophagy is a dynamic process whereby cytoplasmic components are initially sequestered within autophagosomes. Recent studies have shown that the autophagosome membrane can selectively recognize ubiquitinated proteins and organelles through interaction with adapter proteins such as p62 and NBR1. Both proteins are structurally similar at the amino acid level, and bind with ubiquitin and ubiquitinated proteins. Although p62 is incorporated into a wide spectrum of pathological inclusions in various neurodegenerative diseases, abnormalities of NBR1 have not been reported in these diseases. Our immunohistochemical examination revealed that the vast majority of Lewy bodies (LBs) in Parkinson's disease and dementia with LBs (DLB) as well as of glial cytoplasmic inclusions in multiple system atrophy (MSA) were positive for NBR1. Neuronal and glial inclusions in tauopathies and TAR DNA-binding protein of 43kDa proteinopathies were rarely immunolabeled, or were unstained. Using cultured cells bearing LB-like inclusions, formation of α-synuclein aggregates was repressed in cells with NBR1 knockdown. Immunoblot analysis showed that the level of NBR1 was significantly increased by 2.5-fold in MSA, but not in DLB. These findings suggest that NBR1 is involved in the formation of cytoplasmic inclusions in α-synucleinopathy.