Control of aging-associated neurodegeneration via hypothalamic extracellular vesicles containing parathymosin.

Aging-associated neurodegeneration underlies various neurological diseases; however, the neurocrine basis remains poorly understood. Here, we investigate the role of parathymosin (PTMS), a secretory protein with nuclear functions that has recently been identified as a circulating factor in the brain. The results show that loss of PTMS is sufficient to cause severe, age-dependent neurodegeneration and reduced lifespan, whereas hypothalamic PTMS gain of function counteracts aging-associated brain disorders and extends lifespan. PTMS is present in hypothalamic extracellular vesicles (EVs), particularly in subpopulations released by hypothalamic neural stem/progenitor cells (htNSCs). These htNSC-derived EVs carry small nuclear and nucleolar RNAs in a PTMS-associated manner to protect recipient neurons from DNA damage. Therapeutically, these htNSC-derived EVs provide a strong effect against neurodegenerative disorders associated with PTMS deficiency in mouse models, including Alzheimer's disease (AD)-like phenotypes in the 5xFAD model. In conclusion, PTMS possesses anti-neurodegenerative properties, and PTMS-containing hypothalamic EVs are significant in combating aging-associated neurodegenerative diseases.