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doi: 10.1242/10.1242/jcs.00292
Research Article |
-Secretase activity requires the presenilin-dependent trafficking of nicastrin through the Golgi apparatus but not its complex glycosylation
1 Laboratory for Neuronal Cell Biology, Center for Human Genetics,
Gasthuisberg/KULeuven and Flanders Interuniversity Institute for Biotechnology
(VIB), Herestraat 49, 3000 Leuven, Belgium
2 Max-Planck-Institute for Brain Research, Department of Neurochemistry, D-60584
Frankfurt, Germany
Author for correspondence (e-mail:
bart.destrooper{at}med.kuleuven.ac.be)
Accepted 25 November 2002
Nicastrin and presenilin are two major components of the 
-secretase
complex, which executes the intramembrane proteolysis of type I integral
membrane proteins such as the amyloid precursor protein (APP) and Notch.
Nicastrin is synthesized in fibroblasts and neurons as an
endoglycosidase-H-sensitive glycosylated precursor protein (immature
nicastrin) and is then modified by complex glycosylation in the Golgi
apparatus and by sialylation in the trans-Golgi network (mature nicastrin).
These modifications are not observed with exogenously overexpressed nicastrin.
Under normal cell culture conditions, only mature nicastrin is expressed at
the cell surface and binds to the presenilin heterodimers. Mature nicastrin
has a half-life of more than 24 hours. In the absence of presenilin 1 and 2,
nicastrin remains entirely endoglycosidase H sensitive, is retained in the
endoplasmic reticulum and is slowly degraded. Single presenilin 1 or
presenilin 2 deficiency affects glycosylation of nicastrin to a lesser extent
than the combined presenilin deficiencies, suggesting a correlation between
either the transport of nicastrin out of the endoplasmic reticulum or the
concomitant complex glycosylation of nicastrin, and -secretase
activity. However, when complex glycosylation of nicastrin was inhibited using
mannosidase I inhibitors, -secretase cleavage of APP or Notch was not
inhibited and the immature nicastrin still associates with presenilin and
appears at the cell surface. Complex glycosylation of nicastrin is therefore
not needed for -secretase activity. Because the trafficking of
nicastrin to the Golgi apparatus is dependent on presenilins, our data point
to a central role of presenilin in nicastrin maturation/localization, which
could help to partially resolve the `spatial paradox'.
Key words: Nicastrin, Presenilin, -Secretase, Alzheimer's disease, Glycosylation
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