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Exploring the role of BIN1 in Alzheimer’s disease
Author(s) -
Gabriele Rebecca,
Glen Elizabeth,
Wray Selina,
Lines Georgie
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.042794
Subject(s) - atf6 , western blot , unfolded protein response , endoplasmic reticulum , transfection , biology , immunocytochemistry , gene isoform , microbiology and biotechnology , downregulation and upregulation , transcription factor , cell culture , gene , endocrinology , biochemistry , genetics
Background Bridging integrator 1 (BIN1) is a major risk factor for Alzheimer’s disease (AD). In the brain BIN1 is expressed by neurons and glial cells with each cell type expressing specific isoforms. Interestingly, previous studies have shown that BIN1 expression is altered in AD brains. However, little is known on how each individual isoform is affected and how BIN1 contributes to AD pathogenesis. Our preliminary data suggests that the neuronal isoforms of BIN1 (nBIN1) may modulate the unfolded protein response (UPR), an endoplasmic reticulum stress triggered mechanism. The UPR consists of three different signalling pathways regulated by: PERK, IRE1 and the transcription factor ATF6, which is cleaved into an active form which translocates to the nucleus. Interestingly, the UPR is thought to play a role in AD pathogenesis. This study examines the role of BIN1 in AD as UPR modulator. Method Effects of BIN1 expression on UPR activation was investigated by means of western blot and immunocytochemistry in SH‐SY5Y cells expressing nBIN1 or an empty vector. To detect the ATF6 fragment, western blot was carried out on HEK cells expressing BIN1 or an empty vector co‐transfected with an ATF6‐GFP construct. Effects of BIN1 downregulation was explored by luciferase assay and immunocytochemistry in N2a cells transfected with BIN1 or control siRNA Result Increased expression of BIN1 showed a significant decrease in full‐length ATF6, an increase in the cleaved fragment of ATF6, an increase in the ATF6 target gene Bip and a significant increase in ATF6 nuclear translocation compared to control, suggesting a selective activation of the ATF6 arm of the UPR. Interestingly, downregulation of BIN1 in N2a shows a selective inhibition of the ATF6 pathway. Conclusion UPR dysregulation is a salient feature in AD; we explored the involvement of BIN1 in the regulation of the UPR and found that altered levels of BIN1 can selectively modulate the ATF6 pathway. Future studies to dissect the relationship between BIN1 and ATF6 and better understand the underlying mechanisms might offer an insight into future therapeutic targets.