DNAJB6a deficiency induces tau pathology through IRE1α-Xbp1-induced mitochondria dysfunction

Endoplasmic reticulum (ER) stress and mitophagy have been indicated in the early stage of Alzheimer's disease (AD), in which tau hyperphosphorylation is one major pathological alteration. However, the precise mechanism remains unclear. Herein, the study identifies a crucial protein, the DnaJ (Hsp40) homolog, subfamily B, member 6a (DNAJB6a), and elucidates its potential pathogenic role in AD. The DNAJB6 gene is systematically screened using bioinformatics methods, confirming its decreased expression in AD patients' brains. And decreased DNAJB6a was found in the brains of the APP/PS1 mice compared to the control mice. DNAJB6a ^-/- mice exhibited cognitive impairment, synaptic loss and the pathological phenotypes of AD. Depletion of DNAJB6a led to activated ER stress depending on the downregulation of heat shock 70kDa protein 5 (HSPA5). Furthermore, DNAJB6a deficiency induced and accelerated AD-like phenotypes through activating IRE1α-XBP1 induced mitochondria dysfunction. These findings highlight DNAJB6a as a potential key target for preventing AD pathology.