Modulation of ERK1/MAPK3 potentiates ERK nuclear signalling, facilitates neuronal cell survival and improves memory in mouse models of neurodegenerative disorders

Abstract

Cell signalling mechanisms are central to neuronal activity and their dysregulation may lead to neurodegenerative processes and associated cognitive decline. So far, a major effort has been directed toward the dissection of disease specific pathways with the still unmet promise to develop precision medicine strategies. With a different approach, here we show that a selective genetic potentiation of neuronal ERK signalling prevents cell death in vitro and in vivo in the mouse brain while ERK attenuation does the opposite. This neuroprotective effect can also be induced pharmacologically by a cell permeable peptide mimicking the loss of ERK1 MAP kinase, leading to a selective enhancement of ERK2 mediated nuclear cell signalling. The drug treatment prevents neurodegeneration in mouse models of Huntington’s (HD), Alzheimer’s (AD), and Parkinson’s disease (PD). Importantly, the selective potentiation of ERK2 signalling facilitates both structural and synaptic plasticity, enhances cognition in healthy mice and rescues mild cognitive impairments in both models of AD and HD. Altogether, our observation truly represents a remarkable example of a shared molecular mechanism across multiple neurodegenerative disorders and a potentially valuable therapeutic target for neuro-enhancement.

Understanding copy number variations through their genes: a molecular view on 16p11.2 deletion and duplication syndromes

“…Based on this model, ERK1 and ERK2 MAP kinases do not signal with the same intensity and, most importantly, they do not translocate into the nucleus at the same rate (Marchi et al, 2008). In fact, as recently described (Indrigo et al, 2023), ERK1 delays the entry of ERK2 MAPK, the most abundant of the two kinases, by specifically binding to a class of importins, the α1/KPNA2 group. This interaction occurs via the unique N-terminal domain of ERK1 to KPNA2 since this binding can be prevented by the administration of a cell penetrating TAT peptide coupled with the same ERK1 N-term domain.…”

“…Recent evidence indicates that targeting this pathway via pharmacological intervention may be a way forward to treat at least certain symptoms associated to 16p11.2 deletion and duplication. In order to understand the rationale of the potential therapeutic approaches based on ERK signalling modulation, we need to refer to the competitive model of ERK1 and ERK2 interaction, developed over the years by our laboratory (Mazzucchelli et al, 2002;Vantaggiato et al, 2006;Indrigo et al, 2010;Indrigo et al, 2023). Based on this model, ERK1 and ERK2 MAP kinases do not signal with the same intensity and, most importantly, they do not translocate into the nucleus at the same rate (Marchi et al, 2008).…”

“…Either the downregulation of ERK1 expression/activity, via gene knock-out, viral mediated silencing, or via in vivo administration of the RB5 peptide results in neuronal survival, cognitive enhancement and increased structural and synaptic plasticity. Those remarkable effects are the direct cause of a global enhancement of ERK signalling in the brain (Indrigo et al, 2023).…”

“…Interestingly, some genes on 16p11.2 and 22q11.2 regions belong to common molecular pathways. For instance, ERK1 is located on 16p11.2, ERK2 on 22q11.2, and the reciprocal differential expression level for these two effectors of the MAPK signalling cascade has previously been associated with cognitive impairments and neurodevelopmental deficits (Mazzucchelli et al, 2002;Pucilowska et al, 2018;Indrigo et al, 2023). Other examples include the presence of different members of the T-Box family (TBX6 in 16p11.2, TBX1 in 22q11.2), implicated in embryogenesis and development, and members of the H3.3 histone chaperone complex HIRA (HIRA on 22q11.2, HIRIP3 on 16p11.2) responsible for chromatin remodelling and gene transcription.…”

Overlap in synaptic neurological condition susceptibility pathways and the neural pannexin 1 interactome revealed by bioinformatics analyses

“…Although Noel et al (2015) reported that that Mapk3/ERK1 is not involved in tau phosphorylation, another report targeting Mapk3/ERK1 prevented tau hyperphosphorylation and aggregation (Siano et al, 2019). Moreover, Indrigo et al (2018) reported that modulation of Mapk3/ERK1 promoted neuroprotective effects in mouse models of Alzheimer disease, Parkinson disease, and Huntington disease, and facilitated hippocampal synaptic plasticity.…”