| First Author | Lordén G | Year | 2022 |
| Journal | Nat Commun | Volume | 13 |
| Issue | 1 | Pages | 7200 |
| PubMed ID | 36418293 | Mgi Jnum | J:348557 |
| Mgi Id | MGI:7387633 | Doi | 10.1038/s41467-022-34679-7 |
| Citation | Lorden G, et al. (2022) Enhanced activity of Alzheimer disease-associated variant of protein kinase Calpha drives cognitive decline in a mouse model. Nat Commun 13(1):7200 |
| abstractText | Exquisitely tuned activity of protein kinase C (PKC) isozymes is essential to maintaining cellular homeostasis. Whereas loss-of-function mutations are generally associated with cancer, gain-of-function variants in one isozyme, PKCalpha, are associated with Alzheimer's disease (AD). Here we show that the enhanced activity of one variant, PKCalpha M489V, is sufficient to rewire the brain phosphoproteome, drive synaptic degeneration, and impair cognition in a mouse model. This variant causes a modest 30% increase in catalytic activity without altering on/off activation dynamics or stability, underscoring that enhanced catalytic activity is sufficient to drive the biochemical, cellular, and ultimately cognitive effects observed. Analysis of hippocampal neurons from PKCalpha M489V mice reveals enhanced amyloid-beta-induced synaptic depression and reduced spine density compared to wild-type mice. Behavioral studies reveal that this mutation alone is sufficient to impair cognition, and, when coupled to a mouse model of AD, further accelerates cognitive decline. The druggability of protein kinases positions PKCalpha as a promising therapeutic target in AD. |
