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PKN1 Exerts Neurodegenerative Effects in an In Vitro Model of Cerebellar Hypoxic–Ischemic Encephalopathy via Inhibition of AKT/GSK3β Signaling.
- Source :
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Biomolecules (2218-273X) . Nov2023, Vol. 13 Issue 11, p1599. 17p. - Publication Year :
- 2023
-
Abstract
- We recently identified protein kinase N1 (PKN1) as a negative gatekeeper of neuronal AKT protein kinase activity during postnatal cerebellar development. The developing cerebellum is specifically vulnerable to hypoxia-ischemia (HI), as it occurs during hypoxic-ischemic encephalopathy, a condition typically caused by oxygen deprivation during or shortly after birth. In that context, activation of the AKT cell survival pathway has emerged as a promising new target for neuroprotective interventions. Here, we investigated the role of PKN1 in an in vitro model of HI, using postnatal cerebellar granule cells (Cgc) derived from Pkn1 wildtype and Pkn1−/− mice. Pkn1−/− Cgc showed significantly higher AKT phosphorylation, resulting in reduced caspase-3 activation and improved survival after HI. Pkn1−/− Cgc also showed enhanced axonal outgrowth on growth-inhibitory glial scar substrates, further pointing towards a protective phenotype of Pkn1 knockout after HI. The specific PKN1 phosphorylation site S374 was functionally relevant for the enhanced axonal outgrowth and AKT interaction. Additionally, PKN1pS374 shows a steep decrease during cerebellar development. In summary, we demonstrate the pathological relevance of the PKN1-AKT interaction in an in vitro HI model and establish the relevant PKN1 phosphorylation sites, contributing important information towards the development of specific PKN1 inhibitors. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 2218273X
- Volume :
- 13
- Issue :
- 11
- Database :
- Academic Search Index
- Journal :
- Biomolecules (2218-273X)
- Publication Type :
- Academic Journal
- Accession number :
- 173832824
- Full Text :
- https://doi.org/10.3390/biom13111599