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

Indrigo, Marzia, Morella, Ilaria ORCID:, Orellana, Daniel, d'Isa, Raffaele, Papale, Alessandro ORCID:, Parra, Riccardo, Gurgone, Antonia, Lecca, Daniela, Cavaccini, Anna, Tigaret, Cezar M. ORCID:, Cagnotto, Alfredo, Jones, Kimberley, Brooks, Simon ORCID:, Ratto, Gian Michele, Allen, Nicholas D. ORCID:, Lelos, Mariah J. ORCID:, Middei, Silvia, Giustetto, Maurizio, Carta, Anna R., Tonini, Raffaella, Salmona, Mario, Hall, Jeremy ORCID:, Thomas, Kerrie ORCID:, Brambilla, Riccardo ORCID: and Fasano, Stefania ORCID: 2023. Nuclear ERK1/2 signaling potentiation enhances neuroprotection and cognition via Importinα1/KPNA2. EMBO Molecular Medicine 15 (11) , e15984. 10.15252/emmm.202215984

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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 importinα1/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.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Biosciences
Neuroscience and Mental Health Research Institute (NMHRI)
Additional Information: License information from Publisher: LICENSE 1: URL:
Publisher: Wiley Open Access
ISSN: 1757-4676
Funders: Wellcome Trust, MRC
Date of First Compliant Deposit: 5 October 2023
Date of Acceptance: 7 September 2023
Last Modified: 27 Feb 2024 12:40

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