One might view this paper as a companion to a recent discussion of the greater vulnerability of the aged brain to amyloid-β toxicity. Here, researchers point out the dysregulation of RNA splicing in aged neurons, and note its contribution to a greater vulnerability to forms of cell stress. Degenerative aging is formed of many contributions, and every perturbation in normal cell metabolism leaves cells vulnerable to other forms of change and damage. It builds upon itself, degrading function, until some major catastrophe results, both at the level of individual cells and their survival, and at the level of tissues and organs. Addressing the dysregulation of RNA splicing is the subject of a few programs in academia and startup biotech companies such as SENISCA, but these remain at relatively early stages of development.
Aging is one of the most prominent risk factors for neurodegeneration, yet the molecular mechanisms underlying the deterioration of old neurons are mostly unknown. To efficiently study neurodegeneration in the context of aging, we transdifferentiated primary human fibroblasts from aged healthy donors directly into neurons, which retained their aging hallmarks, and we verified key findings in aged human and mouse brain tissue.
Here we show that aged neurons are broadly depleted of RNA-binding proteins, especially spliceosome components. Intriguingly, splicing proteins - like the dementia- and ALS-associated protein TDP-43 - mislocalize to the cytoplasm in aged neurons, which leads to widespread alternative splicing. Cytoplasmic spliceosome components are typically recruited to stress granules, but aged neurons suffer from chronic cellular stress that prevents this sequestration. We link chronic stress to the malfunctioning ubiquitylation machinery, poor HSP90α chaperone activity, and the failure to respond to new stress events.
Together, our data demonstrate that aging-linked deterioration of RNA biology is a key driver of poor resiliency in aged neurons.
Link: https://doi.org/10.1038/s41593-025-01952-z
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