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

Autor: Marzia Indrigo, Ilaria Morella, Daniel Orellana, Raffaele d'Isa, Alessandro Papale, Riccardo Parra, Antonia Gurgone, Daniela Lecca, Anna Cavaccini, Cezar M Tigaret, Alfredo Cagnotto, Kimberley Jones, Simon Brooks, Gian Michele Ratto, Nicholas D Allen, Mariah J Lelos, Silvia Middei, Maurizio Giustetto, Anna R Carta, Raffaella Tonini, Mario Salmona, Jeremy Hall, Kerrie Thomas, Riccardo Brambilla, Stefania Fasano
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: EMBO Molecular Medicine, Vol 15, Iss 11, Pp 1-25 (2023)
Druh dokumentu: article
ISSN: 1757-4676
1757-4684
DOI: 10.15252/emmm.202215984
Popis: Abstract 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.
Databáze: Directory of Open Access Journals
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