Review links aging neuron vulnerability to RNA processing failures

Review links aging neuron vulnerability to RNA processing failures

On 8 September 2026, the journal Trends in Cell Biology published a review on age-related changes in RNA. RNA molecules carry the instructions a cell uses to synthesize proteins. The authors compiled evidence on how age-related failures in RNA processing may make neurons more susceptible to neurodegeneration.

Neurons maintain long projections and modify individual contacts with other cells. This requires them to transport RNA far from the nucleus and synthesize proteins locally. By the review's estimate, regulated RNA transport and local translation supply roughly half of a neuron's proteins.

During splicing, the cell excises certain segments from an RNA molecule and joins others together, producing different variants of the instruction. RNA-binding proteins govern RNA processing, transport, readout, and degradation. With age, their abundance, their position within the cell, and the set of RNAs they interact with can all change. In one experiment, skin cells from elderly healthy donors were directly converted into neurons; in these neurons the RNA-binding protein TDP-43 shifted from the nucleus into the cytoplasm, the cell's internal environment surrounding the nucleus, and the researchers linked this displacement to widespread changes in alternative splicing.

Stress granules are transient assemblies of RNA and proteins. Under stress they help the cell rapidly reorganize protein synthesis and normally dissolve once the stress subsides. The review authors note that aging may alter both their composition and their capacity to dissolve. Some RNAs contain double-stranded regions; innate immune mechanisms can mistake these regions for signs of viral infection and activate an inflammatory response.

Several genes whose variants are associated with ALS and frontotemporal dementia, diseases in which the nervous system progressively loses function, encode RNA-binding proteins. The authors propose a model: under normal conditions a disease-linked variant may have little effect on the cell, while age-related stress erodes the cell's capacity to cope with the burden. Against the background of accumulating age-related changes in RNA and protein homeostasis, the variant's effect may become amplified.

The authors suggest selectively altering individual RNA regulators in laboratory neuron models and measuring the impact on cell function. Such experiments should identify which age-related disruptions in RNA regulation are themselves sufficient to impair neuronal performance.