Summary Ras and Rap small GTPases are important for synaptic plasticity and memory. However, their roles in homeostatic plasticity are unknown. Here, we report that polo-like kinase 2 (Plk2), a homeostatic suppressor of overexcitation, governs the activity of Ras and Rap via coordination of their regulatory proteins. Plk2 directs elimination of Ras activator RasGRF1 and Rap inhibitor SPAR via phosphorylation-dependent ubiquitin-proteasome degradation. Conversely, Plk2 phosphorylation stimulates Ras inhibitor SynGAP and Rap activator PDZGEF1. These Ras/Rap regulators perform complementary functions to downregulate dendritic spines and AMPA receptors following elevated activity, and their collective regulation by Plk2 profoundly stimulates Rap and suppresses Ras. Furthermore, perturbation of Plk2 disrupts Ras and Rap signaling, prevents homeostatic shrinkage and loss of dendritic spines, and impairs proper memory formation. Our study demonstrates a critical role of Plk2 in the synchronized tuning of Ras and Rap, and underscores the functional importance of this regulation in homeostatic synaptic plasticity.
Alzheimer disease (AD) is a neurodegenerative disorder characterized by pathological hallmarks of neurofibrillary tangles and amyloid plaques. The plaques are formed by aggregation and accumulation of amyloid β (Aβ), a cleavage fragment of amyloid precursor protein (APP). Enhanced neuronal activity and seizure events are frequently observed in AD, and elevated synaptic activity promotes Aβ production. However, the mechanisms that link synaptic hyperactivity to APP processing and AD pathogenesis are not well understood. We previously found that Polo-like kinase 2 (Plk2), a homeostatic repressor of neuronal overexcitation, promotes APP β-processing in vitro . Here, we report that Plk2 stimulates Aβ production in vivo , and that Plk2 levels are elevated in a spatiotemporally regulated manner in brains of AD mouse models and human AD patients. Genetic disruption of Plk2 kinase function reduces plaque deposits and activity-dependent Aβ production. Furthermore, pharmacological Plk2 inhibition hinders Aβ formation, synapse loss, and memory decline in an AD mouse model. Thus, Plk2 links synaptic overactivity to APP β-processing, Aβ production, and disease-relevant phenotypes in vivo , suggesting that Plk2 may be a potential target for AD therapeutics.
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