Aβ modulates actin cytoskeleton via SHIP2-mediated phosphoinositide metabolism

Title
Aβ modulates actin cytoskeleton via SHIP2-mediated phosphoinositide metabolism
Authors
배애님성지혜류훈주정민김현빈이해님심경미박재봉
Issue Date
2019-10
Publisher
Scientific Reports
Citation
VOL 9-15557-12
Abstract
Emerging evidences suggest that phospholipid metabolism is altered in Alzheimer’s disease (AD), but molecular mechanisms on how this affects neurodegeneration in AD is poorly understood. SHIP2 is a phosphoinositide-metabolizing enzyme, which dephosphorylates PI(3,4,5)P3 resulting to PI(3,4)P2, and it has been recently shown that Aβ directly increases the activity of SHIP2. Here we monitored, utilizing fluorescent SHIP2 biosensor, real-time increase of PI(3,4)P2-containing vesicles in HT22 cells treated with Aβ. Interestingly, PI(3,4)P2 is accumulated at late endosomes and lysosomal vesicles. We further discovered that ARAP3 can be attracted to PI(3,4)P2-positive mature endosomes via its PH domain and this facilitates the degradation of ARAP3. The reduced level of ARAP3 then causes RhoA hyperactivation and filamentous actin, which are critical for neurodegeneration in AD. These results provide a novel molecular link between Aβ and actin disruption through dysregulated phosphoinositide metabolism, and the SHIP2-PI(3,4)P2-ARAP3-RhoA signaling pathway can be considered as new therapeutic targets for synaptic dysfunctions in Alzheimer’s disease.
URI
http://pubs.kist.re.kr/handle/201004/70869
ISSN
2045-2322
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KIST Publication > Article
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