PUBLICATION

Unraveling Presenilin 2 Functions in a Knockout Zebrafish Line to Shed Light into Alzheimer's Disease Pathogenesis

Authors
Barazzuol, L., Cieri, D., Facchinello, N., Calì, T., Washbourne, P., Argenton, F., Pizzo, P.
ID
ZDB-PUB-230212-25
Date
2023
Source
Cells   12(3): (Journal)
Registered Authors
Argenton, Francesco, Facchinello, Nicola, Washbourne, Philip
Keywords
Alzheimer’s disease, ER-mitochondria contacts, autophagy, mitochondrial axonal transport, presenilin 2, zebrafish
MeSH Terms
  • Alzheimer Disease*/metabolism
  • Amyloid Precursor Protein Secretases/metabolism
  • Animals
  • Humans
  • Mammals/metabolism
  • Presenilin-2/genetics
  • Presenilin-2/metabolism
  • Zebrafish*/genetics
  • Zebrafish*/metabolism
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed
36766721 Full text @ Cells
Abstract
Mutations in presenilin 2 (PS2) have been causally linked to the development of inherited Alzheimer's disease (AD). Besides its role as part of the γ-secretase complex, mammalian PS2 is also involved, as an individual protein, in a growing number of cell processes, which result altered in AD. To gain more insight into PS2 (dys)functions, we have generated a presenilin2 (psen2) knockout zebrafish line. We found that the absence of the protein does not markedly influence Notch signaling at early developmental stages, suggesting a Psen2 dispensable role in the γ-secretase-mediated Notch processing. Instead, loss of Psen2 induces an exaggerated locomotor response to stimulation in fish larvae, a reduced number of ER-mitochondria contacts in zebrafish neurons, and an increased basal autophagy. Moreover, the protein is involved in mitochondrial axonal transport, since its acute downregulation reduces in vivo organelle flux in zebrafish sensory neurons. Importantly, the expression of a human AD-linked mutant of the protein increases this vital process. Overall, our results confirm zebrafish as a good model organism for investigating PS2 functions in vivo, representing an alternative tool for the characterization of new AD-linked defective cell pathways and the testing of possible correcting drugs.
Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping