|  Help  |  About  |  Contact Us

Publication : ATAD3A oligomerization promotes neuropathology and cognitive deficits in Alzheimer's disease models.

First Author  Zhao Y Year  2022
Journal  Nat Commun Volume  13
Issue  1 Pages  1121
PubMed ID  35236834 Mgi Jnum  J:342927
Mgi Id  MGI:7255918 Doi  10.1038/s41467-022-28769-9
Citation  Zhao Y, et al. (2022) ATAD3A oligomerization promotes neuropathology and cognitive deficits in Alzheimer's disease models. Nat Commun 13(1):1121
abstractText  Predisposition to Alzheimer's disease (AD) may arise from lipid metabolism perturbation, however, the underlying mechanism remains elusive. Here, we identify ATPase family AAA-domain containing protein 3A (ATAD3A), a mitochondrial AAA-ATPase, as a molecular switch that links cholesterol metabolism impairment to AD phenotypes. In neuronal models of AD, the 5XFAD mouse model and post-mortem AD brains, ATAD3A is oligomerized and accumulated at the mitochondria-associated ER membranes (MAMs), where it induces cholesterol accumulation by inhibiting gene expression of CYP46A1, an enzyme governing brain cholesterol clearance. ATAD3A and CYP46A1 cooperate to promote APP processing and synaptic loss. Suppressing ATAD3A oligomerization by heterozygous ATAD3A knockout or pharmacological inhibition with DA1 restores neuronal CYP46A1 levels, normalizes brain cholesterol turnover and MAM integrity, suppresses APP processing and synaptic loss, and consequently reduces AD neuropathology and cognitive deficits in AD transgenic mice. These findings reveal a role for ATAD3A oligomerization in AD pathogenesis and suggest ATAD3A as a potential therapeutic target for AD.
Quick Links:
 
Quick Links:
 

Expression

Publication --> Expression annotations

 

Other

18 Bio Entities

0 Expression