Enhanced activity of Alzheimer disease-associated variant of protein kinase Cα drives cognitive decline in a mouse model

Gema Lordén, Jacob M. Wozniak, Kim Doré, Lara E. Dozier, Chelsea Cates-Gatto, Gentry N. Patrick, David J. Gonzalez, Amanda J. Roberts, Rudolph E. Tanzi and Alexandra C. Newton ()
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Gema Lordén: University of California San Diego
Jacob M. Wozniak: University of California San Diego
Kim Doré: University of California San Diego
Lara E. Dozier: University of California San Diego
Chelsea Cates-Gatto: The Scripps Research Institute
Gentry N. Patrick: University of California San Diego
David J. Gonzalez: University of California San Diego
Amanda J. Roberts: The Scripps Research Institute
Rudolph E. Tanzi: Massachusetts General Hospital and Harvard Medical School
Alexandra C. Newton: University of California San Diego

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract 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, PKCα, are associated with Alzheimer’s disease (AD). Here we show that the enhanced activity of one variant, PKCα 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 PKCα M489V mice reveals enhanced amyloid-β-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 PKCα as a promising therapeutic target in AD.

Date: 2022
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DOI: 10.1038/s41467-022-34679-7

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