ABSTRACT
INTRODUCTION As the world population ages, new molecular targets in aging and Alzheimer’s Disease (AD) are needed to combat the expected influx of new AD cases. Until now, the role of RNA structure in aging and neurodegeneration has largely remained unexplored. METHODS: In this study, we examined human hippocampal postmortem tissue for the formation of RNA G-quadruplexes (rG4s) in aging and AD.
RESULTS We found that rG4 immunostaining strongly increased in the hippocampus with both age and with AD severity. We further found that neurons with accumulation of phospho-tau immunostaining contained rG4s, that rG4 structure can drive tau aggregation, and that rG4 staining density depended on APOE genotype in the human tissue examined.
DISCUSSION Combined with previous studies showing the dependence of rG4 structure on stress and the extreme power of rG4s at oligomerizing proteins, we propose a model of neurodegeneration in which chronic rG4 formation drives proteostasis collapse. These morphological findings suggest that further investigation of RNA structure in neurodegeneration is a critical avenue for future treatments and diagnoses.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
All figures require color printing.
Largest change is adding new panels to Fig 3 (now a and b) that show that much of the G-quadruplex staining arises ribosomal rRNA G-quadruplexes.
