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bioRxiv · 10.64898/2026.03.19.712974

Janus kinase 2 regulates Nurr1 protein stability in dopaminergic neurons of the aging midbrain

Jang, Y.·Kim, Y. H.·Jeon, J.·Cha, Y.·Lopes, C.·Jung, J. H.·Oh, E.·Park, Y.·Ko, C.·Hyeon, B.·Leblanc, P.·Kim, K.-S.
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Abstract

The nuclear receptor Nurr1 (NR4A2) is an essential transcription factor that governs the differentiation, maturation, and long-term maintenance of midbrain dopaminergic (mDA) neurons in the substantia nigra. Reduced Nurr1 expression has been closely linked to age-related dopaminergic neuronal loss and the pathogenesis of Parkinsons disease. However, the molecular mechanisms regulating Nurr1 expression and protein stability in the aging midbrain remain poorly understood. Here, we identify Janus kinase 2 (JAK2) as a previously unrecognized regulator of Nurr1 in mDA neurons. In the substantia nigra of aged mice (12-and 18-month-old), JAK2 was robustly expressed in Nurr1-positive mDA neurons, whereas its expression was minimal in young adult mice. In SK-N-BE(2)C neuroblastoma cells, overexpression of JAK2 modestly enhanced Nurr1 transcriptional activity, while the constitutively active mutant JAK2V617F markedly increased it. Notably, this effect was not blocked by pharmacological inhibition of STAT, PI3K, or Akt signaling pathways, indicating that JAK2 regulates Nurr1 independently of canonical JAK/STAT or PI3K/Akt signaling. Mechanistically, JAK2 did not promote tyrosine phosphorylation of Nurr1 but instead physically interacted with Nurr1, leading to enhanced nuclear stability of the Nurr1 protein. Consistent with this mechanism, expression of JAK2V617F increased Nurr1 protein levels without altering its mRNA expression. Functionally, co-expression of JAK2V617F and Nurr1 attenuated oxidative stress-induced cytotoxicity and reduced reactive oxygen species accumulation. Together, these findings reveal a phosphorylation-independent mechanism by which JAK2 stabilizes Nurr1 protein and enhances its transcriptional activity. Our results further suggest that age-associated induction of JAK2 in dopaminergic neurons may promote neuronal resilience by maintaining Nurr1 protein stability during aging.

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Jang, Y., Kim, Y. H., Jeon, J., Cha, Y., Lopes, C., Jung, J. H., Oh, E., Park, Y., Ko, C., Hyeon, B., Leblanc, P., Kim, K.-S.. 2026-03-23. Janus kinase 2 regulates Nurr1 protein stability in dopaminergic neurons of the aging midbrain. https://doi.org/10.64898/2026.03.19.712974

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