Presenilin 2 mutations alter cystatin C trafficking in mouse primary neurons.
Mutations in the presenilin genes account for the majority of familial Alzheimer disease (FAD) cases. In the present report we demonstrated that the FAD-linked presenilin 2 mutations (PS2 M239I and T122R) alter cystatin C trafficking in mouse primary neurons reducing secretion of its glycosylated form. These mutations showed a different impact on cystatin C: PS2 T122R had a much stronger effect determining a dramatic intracellular accumulation of cystatin C (native and glycosylated), followed by a reduction in the secretion of both forms. Several experimental evidences suggest that cystatin C exerts a protective role in the brain and favors stem cells proliferation. Confocal imaging showed that the effect of PS2 T122R mutation was a massive recruitment of cystatin C into the neuronal processes, in the presence of an intact cytoskeletal structure. The consequent reduction in the cystatin C extracellular levels might result in a failure of neuroregeneration. Understanding the interplay of PS2 and cystatin C in the pathogenesis of AD might highlight new therapeutic prospective.
Ghidoni
Roberta
R
NeuroBioGen Lab-Memory Clinic, IRCCS Centro S. Giovanni di Dio-FBF, AFaR, Brescia, Italy.
Benussi
Luisa
L
Paterlini
Anna
A
Missale
Cristina
C
Usardi
Alessia
A
Rossi
Rossana
R
Barbiero
Laura
L
Spano
Pierfranco
P
Binetti
Giuliano
G
D000818:Animals; D001120:Arginine / Q000235:genetics; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D055316:Cystatin C; D015891:Cystatins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007532:Isoleucine / Q000235:genetics; D008715:Methionine / Q000235:genetics; D051379:Mice; D018613:Microscopy, Confocal / Q000379:methods; D009154:Mutation / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D053766:Presenilin-2 / Q000235:genetics*; D021381:Protein Transport / Q000235:genetics; D013912:Threonine / Q000235:genetics; D014162:Transfection / Q000379:methods; D014404:Tubulin / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
C525030:CST3 protein, human; C525031:Cst3 protein, mouse; D055316:Cystatin C; D015891:Cystatins; D053766:Presenilin-2; D014404:Tubulin; D016875:tau Proteins; D007532:Isoleucine; D013912:Threonine; D001120:Arginine; D008715:Methionine