Nuclear ERK1/2 signaling potentiation enhances neuroprotection and cognition via Importinα1/KPNA2

Cell signaling is central to neuronal activity and its dysregulation may lead to neurodegeneration and cognitive decline. Here, we show that selective genetic potentiation of neuronal ERK signaling prevents cell death in vitro and in vivo in the mouse brain, while attenuation of ERK signaling does the opposite. This neuroprotective effect mediated by an enhanced nuclear ERK activity can also be induced by the novel cell penetrating peptide RB5. In vitro administration of RB5 disrupts the preferential interaction of ERK1 MAP kinase with importin alpha 1/KPNA2 over ERK2, facilitates ERK1/2 nuclear translocation, and enhances global ERK activity. Importantly, RB5 treatment in vivo promotes neuroprotection in mouse models of Huntington's (HD), Alzheimer's (AD), and Parkinson's (PD) disease, and enhances ERK signaling in a human cellular model of HD. Additionally, RB5-mediated potentiation of ERK nuclear signaling facilitates synaptic plasticity, enhances cognition in healthy rodents, and rescues cognitive impairments in AD and HD models. The reported molecular mechanism shared across multiple neurodegenerative disorders reveals a potential new therapeutic target approach based on the modulation of KPNA2-ERK1/2 interactions.imageShared mechanisms governing both neuronal cell survival and neuroplasticity have not yet been explored therapeutically. This study demonstrates that modulation of ERK1 and KPNA2 interactions strengthens nuclear ERK signaling in the brain, promotes cognitive enhancement, and delays neurodegeneration.Genetic approaches altering ERK1 and ERK2 MAP kinase ratio, enhance global ERK signaling and attenuate neuronal cell death in vitro and in vivo.A cell penetrating peptide (RB5), designed around the unique N-terminal domain of ERK1 MAP kinase, enhances nuclear ERK signaling in cells and in the mouse brain by mimicking ERK1 downregulation.RB5 prevents ERK1 interactions with the nuclear importin alpha KPNA2 and facilitates nuclear entry of the main Kinase ERK2.RB5 prevents synaptic dysfunction and neuronal cell death in mouse models of Huntington's, Alzheimer's and Parkinson's Disease.RB5 enhances memory formation and consolidation and facilitates synaptic plasticity in normal mice and models of neurodegeneration.Shared mechanisms governing both neuronal cell survival and neuroplasticity have not yet been explored therapeutically. This study demonstrates that modulation of ERK1 and KPNA2 interactions strengthens nuclear ERK signaling in the brain, promotes cognitive enhancement, and delays neurodegeneration.imag