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Bardet-Biedl syndrome (BBS) is an autosomal recessive syndrome presenting with retinal dystrophy, cognitive impairment, and obesity. BBS is characterized by elevated endoplasmic reticulum (ER) stress in the early stages of adipocyte and retinal development. BBS expression in the CNS and indications of hippocampal dysgenesis suggest neural development abnormalities. However, the role of BBS in ER stress in neuronal cells has not yet been studied. Therefore, we aimed at studying the role of BBS4 in neuronal development under normal and ER stress conditions. ER stress and unfolded protein response (UPR) were studied in BBS4-silenced (SiBBS4) SH-SY5Y cells during differentiation under normal and stress states, using molecular and biochemical markers. ER stress was demonstrated at early neural differentiation, with significantly augmented expression of UPR markers corresponding to BBS4 expression. In the undifferentiated state, BBS4 silencing resulted in significantly reduced ER-stress markers' expression under normal and ER-stress states. Independent of ER stress, SiBBS4 cells demonstrated significant reduction in activated phospho-IRE1α. Under BBS4 silencing, both sXBP-1 and activated ATF6α p50 failed to translocate to the nucleus. Transcript levels of apoptosis markers were upregulated under BBS4 depletion and ER-stress induction, corresponding to decreased viability. BBS4 depletion in neuronal cells results in reduced sensitivity to ER stress during differentiation and under ER-stress induction, partly due to failure in translocation of ER-transcription factors (TF) sXBP-1 and ATF6α p50 to the nucleus. Hence, BBS4 is essential for nuclear transport under ER-stress response in neuronal cells during early differentiation. Our studies shed light on molecular mechanisms through which BBS4 malfunction alters neuronal ER stress response.


Avital Horwitz, Ruth Birk. BBS4 Is Essential for Nuclear Transport of Transcription Factors Mediating Neuronal ER Stress Response. Molecular neurobiology. 2021 Jan;58(1):78-91

PMID: 32894499

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