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bioRxiv · 10.64898/2026.09.09.750353

Exosomal miR-23a release coincides with astrocytic calcineurin activation, protects neurons from apoptosis by regulating NOXA in Parkinson's disease models and is enriched in the plasma of patients with Parkinson's disease

Bhattacharyya, P.·Gharami, K.·Biswas, A.·Biswas, S. C.
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Abstract

Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta and degeneration of their projections in the striatum (STR) of the brain. Astrocytes are recognized as active contributors to PD pathogenesis, yet the role of calcineurin (CN), a Ca/calmodulin-dependent phosphatase which is well characterized in neurons, remains unexplored in astrocytes in the context of PD. Here, we show that CN protein expression is upregulated in the STR of MPTP-treated mice, coinciding with DA neurodegeneration and astrogliosis. In human astrocytoma cells and primary rat astrocytes, the neurotoxin Rotenone induced rapid intracellular Calcium elevation and CN activation. Unexpectedly, this was accompanied by a decrease in intracellular levels of miR-23a, an astrocyte-enriched microRNA previously linked to CN signalling in cardiomyocytes. We found that this decrease reflected active exosomal export: Rotenone increased both exosomal miR-23a levels and total exosome number, while blocking exosome biogenesis with GW4869 restored intracellular miR-23a levels. Functionally, both astrocyte-derived exosomes and miR-23a overexpression protected neuronal cells (SH-SY5Y, PC12) against Rotenone-, 6-OHDA-, and MPP+-induced toxicity. Mechanistically, miR-23a showed direct binding to the 3'UTR of the pro-apoptotic BH3-only protein NOXA, thereby suppressing its expression, subsequently attenuating caspase-3 activation. Finally, exosomal miR-23a levels were significantly elevated in plasma from PD patients compared with age-matched controls, supporting clinical relevance. Together, these findings identify a previously unrecognized astrocyte-to-neuron communication axis during PD pathogenesis, in which astrocytic CN activation accompanied by exosomal miR-23a release represents a neuroprotective stress-responsive pathway with potential biomarker and therapeutic relevance in PD.

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Bhattacharyya, P., Gharami, K., Biswas, A., Biswas, S. C.. 2026-09-15. Exosomal miR-23a release coincides with astrocytic calcineurin activation, protects neurons from apoptosis by regulating NOXA in Parkinson's disease models and is enriched in the plasma of patients with Parkinson's disease. https://doi.org/10.64898/2026.09.09.750353

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