ELAVL Proteins, miRNA Fate, and Extracellular RNA Communication in Brain Aging and Neurodegeneration

Abstract

Highlights What are the main findings? ELAVL proteins connect intracellular miRNA regulation with extracellular RNA communication. HuD promotes let-7a and miR-125b export during neuronal differentiation. HuR regulates selected miRNAs through intracellular buffering and endosomal export. ELAVL–miRNA–EV signaling in brain aging and neurodegeneration remains a testable framework. What are the implications of the main findings? ELAVL proteins may determine whether selected miRNAs remain active, are buffered, or are exported in EVs. Altered HuD/HuR activity could disrupt neuronal RNA homeostasis and neuron–glia communication. This framework may explain the context-dependent protective and pathogenic effects of HuD. Selective ELAVL–miRNA interactions may offer future therapeutic targets in neurodegeneration. Abstract Brain aging is accompanied by changes in RNA homeostasis, intercellular communication, and stress responses that increase vulnerability to neurodegenerative diseases. The neuronal protein HuD (ELAVL4) and the broadly expressed HuR (ELAVL1) regulate RNA stability, translation, localization, and selected microRNA (miRNA) activities. Recent studies further show that HuD can promote export of let-7a and miR-125b during differentiation of PC12 cells, whereas HuR can bind selected miRNAs and engage endosomal export or intracellular buffering mechanisms in other cellular contexts. These observations support an emerging ELAVL–miRNA–extracellular vesicle (EV) framework. They do not yet establish an integrated HuD/HuR-dependent neuron–glia pathway in aging human brain or Alzheimer’s disease (AD). We therefore distinguish direct, model-specific findings from hypotheses that age-, amyloid-, or inflammation-associated changes in ELAVL abundance, localization, or RNA binding could redistribute miRNAs between intracellular pools and EVs. Testing this framework in primary human neural cells, induced pluripotent stem cell-derived systems, organoids, and in vivo models may identify context-specific mechanisms and therapeutic opportunities.