Colocalization of BRCA1 with Tau Aggregates in Human Tauopathies.

Masanori Kurihara,Tatsuo Mano,Atsushi Iwata,Tatsushi Toda,Yuko Saito,Shigeo Murayama

doi:10.3390/brainsci10010007

Abstract

The mechanism of neuronal dysfunction via tau aggregation in tauopathy patients is controversial. In Alzheimer’s disease (AD), we previously reported mislocalization of the DNA repair nuclear protein BRCA1, its coaggregation with tau, and the possible importance of the subsequent DNA repair dysfunction. However, whether this dysfunction in BRCA1 also occurs in other tauopathies is unknown. The aim of this study was to evaluate whether BRCA1 colocalizes with tau aggregates in the cytoplasm in the brains of the patients with tauopathy. We evaluated four AD, two Pick’s disease (PiD), three progressive supranuclear palsy (PSP), three corticobasal degeneration (CBD), four normal control, and four disease control autopsy brains. Immunohistochemistry was performed using antibodies against BRCA1 and phosphorylated tau (AT8). Colocalization was confirmed by immunofluorescence double staining. Colocalization of BRCA1 with tau aggregates was observed in neurofibrillary tangles and neuropil threads in AD, pick bodies in PiD, and globose neurofibrillary tangles and glial coiled bodies in PSP. However, only partial colocalization was observed in tuft-shaped astrocytes in PSP, and no colocalization was observed in CBD. Mislocalization of BRCA1 was not observed in disease controls. BRCA1 was mislocalized to the cytoplasm and colocalized with tau aggregates in not only AD but also in PiD and PSP. Mislocalization of BRCA1 by tau aggregates may be involved in the pathogenesis of PiD and PSP.

Highlights

Tauopathies, including Alzheimer’s disease (AD), Pick’s disease (PiD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), are neurodegenerative disorders characterized by aggregated tau protein deposition in the brain
In AD, we previously reported that tau may cause neuronal dysfunction by coaggregation with BRCA1
Brain regions containing characteristic protein inclusions, namely, the medial temporal lobe for AD, normal controls (NC), dementia with Lewy bodies (DLB), and Parkinson’s disease with dementia (PDD), frontal lobe for PiD and multiple system atrophy cerebellar type (MSA-C), precentral gyrus and midbrain for PSP and CBD, and precentral gyrus for amyotrophic lateral sclerosis (ALS), were used for further assessment

Summary

Introduction

Tauopathies, including Alzheimer’s disease (AD), Pick’s disease (PiD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), are neurodegenerative disorders characterized by aggregated tau protein deposition in the brain. Each tauopathy shows characteristic tau deposition either composed of the three-repeat (3R) isoform of tau, four-repeat (4R) isoform of tau, or both [1]. The extent of tau deposition correlates with neuronal loss and clinical symptoms and is considered the major cause of these diseases. The mechanism of neuronal dysfunction and neuronal loss via tau aggregation remains controversial. In AD, we previously reported that tau may cause neuronal dysfunction by coaggregation with BRCA1. BRCA1 is encoded by the BRCA1 gene, which is known to cause hereditary breast

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