Key gene in familial Alzheimer’s disease regulates neuronal development

Summary: Researchers identify a new cell mechanism that connects Alzheimer’s disease and cancers.

Source: UAB

Age is the most important factor in the development of neurodegenerative diseases such as Alzheimer’s and cancer. Moreover, epidemiological studies indicate that there is an inverse correlation between suffering from Alzheimer’s disease and cancer, although the mechanisms connecting these two pathologies remain unknown.

An international team of researchers led by Dr Carles Saura from the Institute of Neuroscience at UAB has unravel a mechanism crucial for the growth of neuron axons, a key process for the correct development of the brain.

According to the study, published in eLife, this mechanism requires presenilin, the main gene mutated in familial Alzheimer’s disease. Its malfunction in this disease is what causes the abnormal accumulation of beta-amyloid in the brain in Alzheimer’s disease patients. In this study, researchers demonstrate that presenilin is not only essential for regulating growth of neurons during brain development, but that it achieves this through the EphA3 receptor, a protein involved in several cancers. The relevance of this study is that it demonstrates the existence of a new cell mechanism that connects neurodegeneration with cancer.

This is a hippocampal brain slice

This image shows the developing brain visualized with fluorescence laser scanning microscopy. It illustrates the neurons (blue) and growing axons (red and green). The image is credited to INc-UAB.

“The discovery of this new signalling route is very relevant in the study of neurological disorders in which the morphology of the neuron axon is altered. Indeed, the implications of the study go beyond the brain given that the mechanism involves the EphA receptors, which play a key role in cancer”, explains first author of the study Dr. Míriam Javier. According to Dr. Saura, “this research allows us to be optimistic about the development of common therapeutic strategies to fight neurological disorders and cancer.”

About this neuroscience research article

Source:
UAB
Media Contacts:
Roser Bastida Barau – UAB
Image Source:
The image is credited to INc-UAB.

Original Research: Open access
“Presenilin/γ-secretase-dependent EphA3 processing mediates axon elongation through non-muscle myosin IIA”. Míriam Javier-Torrent, Sergi Marco, Daniel Rocandio, Maria Pons-Vizcarra, Peter W Janes, Martin Lackmann, Joaquim Egea, Carlos A Saura.
eLife doi:10.7554/eLife.43646.

Abstract

Presenilin/γ-secretase-dependent EphA3 processing mediates axon elongation through non-muscle myosin IIA

EphA/ephrin signaling regulates axon growth and guidance of neurons, but whether this process occurs also independently of ephrins is unclear. We show that presenilin-1 (PS1)/γ-secretase is required for axon growth in the developing mouse brain. PS1/γ-secretase mediates axon growth by inhibiting RhoA signaling and cleaving EphA3 independently of ligand to generate an intracellular domain (ICD) fragment that reverses axon defects in PS1/γ-secretase- and EphA3-deficient hippocampal neurons. Proteomic analysis revealed that EphA3 ICD binds to non-muscle myosin IIA (NMIIA) and increases its phosphorylation (Ser1943), which promotes NMIIA filament disassembly and cytoskeleton rearrangement. PS1/γ-secretase-deficient neurons show decreased phosphorylated NMIIA and NMIIA/actin colocalization. Moreover, pharmacological NMII inhibition reverses axon retraction in PS-deficient neurons suggesting that NMIIA mediates PS/EphA3-dependent axon elongation. In conclusion, PS/γ-secretase-dependent EphA3 cleavage mediates axon growth by regulating filament assembly through RhoA signaling and NMIIA, suggesting opposite roles of EphA3 on inhibiting (ligand-dependent) and promoting (receptor processing) axon growth in developing neurons.

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