Mutations in the presenilin 1 (PSEN1) gene are a major cause of presenile a
utosomal dominant Alzheimer's disease (AD). The amount of stable, proteolys
ed PSEN1 fragments integrated into a larger 250 kDa membrane-bound protein
complex is very tightly regulated. Proteosomal degradation of excess PSEN1
in particular polyubiquitinylated full-length PSEN1 was established in diff
erent cell lines. We previously demonstrated direct physical interaction be
tween PSEN1 and HC5/ZETA, two subunits of the 20S catalytic particle of the
26S proteasome. Here, we show co-localization between PSEN1 and overexpres
sed HC5/ZETA and between PSEN1 and the endogenous 20S particle in the perin
uclear region of PSEN1 over-expressing Neuro2a and HEK 293 cells. Co-locali
zation was independent of the presence of pathogenic mutations in PSEN1. In
hibition of proteasomal activity in stable PSEN1 transfected HEK 293 cells
resulted in a small increase in perinuclear PSEN1 immunoreactivity, althoug
h no aggresome-like structures were observed. Finally, in hippocampal brain
tissue sections, in vivo intraneuronal perinuclear co-localization between
PSEN1 and the 20S proteasome was observed both in PSEN1 AD and in control
brains.