Aberrant accumulation of phosphorylated BRCA1 in brainstem-type and cortical-type Lewy bodies in Lewy body disease.

Abstract

BRCA1 plays important roles in several biological events during the DNA damage response (DDR). We aimed to determine whether cytoplasmic accumulation of BRCA1 or its phosphorylated form, pBRCA1, is specific to cytoplasmic inclusions in tauopathies, or if it also occurs in α-synuclein-positive inclusions in Lewy body disease (LBD). Using brain tissue from pure LBD, LBD with Alzheimer disease (AD) co-pathology (LBD-AD), and control cases, the immunohistochemical distributions of BRCA1, pBRCA1, its binding partner BARD1, and 53BP1 were examined. The results showed that pBRCA1 (Ser1423) and BARD1 accumulated in brainstem-type Lewy bodies (LBs), whereas only pBRCA1 (Ser1423) was present in cortical-type LBs. There was no significant difference in the frequency of pBRCA1 (Ser1423)-positive LBs between the pure LBD and LBD-AD cases. pBRCA1 (Ser1423) was minimally detected in neuronal nuclei in controls and was absent in neuronal nuclei in LBD cases. In control and LBD cases, 53BP1-immunoreactive deposits were present in the neuronal nuclei. Thus, DDR dysfunction due to cytoplasmic sequestration of pBRCA1 (Ser1423) may play a role in LBD pathogenesis. Additionally, the selective accumulation of BARD1 in brainstem-type LBs, but not cortical-type LBs, points to distinct mechanisms in the formation of these inclusion types, offering further insights into LBD pathology.