Alzheimer disease-associated cystatin C variant undergoes impaired secretion.
CST3 is the coding gene for cystatin C (CysC). CST3 B/B homozygosity is associated with an increased risk of developing Alzheimer disease. We performed CysC analysis on human primary skin fibroblasts obtained from donors carrying A/A, A/B, and B/B CST3. Pulse-chase experiments demonstrated that the release of the B variant of CysC has a different temporal pattern compared to that of the A one. Fibroblasts B/B homozygous displayed a reduced secretion of CysC due to a less efficient cleavage of the signal peptide, as suggested by high-resolution Western blot analysis and by in vitro assay. In the brain, the reduced level of CysC may represent the molecular factor responsible for the increased risk of Alzheimer disease.
Benussi
Luisa
L
Neurobiology Lab, IRCCS Centro San Giovanni di Dio, Italy.
Ghidoni
Roberta
R
Steinhoff
Tiana
T
Alberici
Antonella
A
Villa
Aldo
A
Mazzoli
Federica
F
Nicosia
Francesca
F
Barbiero
Laura
L
Broglio
Laura
L
Feudatari
Enrica
E
Signorini
Simona
S
Finckh
Ulrich
U
Nitsch
Roger M
RM
Binetti
Giuliano
G
D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D015153:Blotting, Western; D002478:Cells, Cultured; D055316:Cystatin C; D015891:Cystatins / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D021382:Protein Sorting Signals / Q000502:physiology; D012867:Skin / Q000166:cytology
C525030:CST3 protein, human; D055316:Cystatin C; D015891:Cystatins; D021382:Protein Sorting Signals