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bioRxiv · 10.64898/2026.10.21.760838

Dysregulation of miR-103a-3p/AGFG1 axis links endocytic trafficking dysfunction to ER stress in Parkinson's disease

Zhang, Z. W.·Chia, S.-Y.·Wong, L. J.·Li, Z.·Tu, H.·Tan, E.-K.·Zhou, Z.·Cao, M.·Zeng, L.
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Abstract

Background: Parkinson's disease is defined by progressive dopaminergic neurodegeneration and -synuclein pathology. Endoplasmic reticulum (ER) stress and clathrin-mediated endocytosis dysfunction are implicated in disease pathogenesis, but the molecular mechanisms connecting these processes remain poorly understood. Here, we investigate a miR-103a-3p/AGFG1 axis as a regulator link between endocytic trafficking and ER stress in Parkinson's disease. Methods: MiR-103a-3p and AGFG1 were examined in plasma and postmortem substantia nigra from patients with Parkinson's disease and controls. Gain- and loss-of-function studies, target validation and live-cell imaging were used to define the role of the miR-103a-3p/AGFG1 axis in ER stress and endocytic trafficking. The pathway was further investigated in SNCA A53T and LRRK2 G2019S hiPSC-derived neurons. Therapeutic targeting of AGFG1 was evaluated using antisense oligonucleotides (ASOs) in vitro and in a 6-hydroxydopamine mouse model. Results: MiR-103a-3p was significantly reduced in Parkinson's disease plasma and substantia nigra, whereas AGFG1 was increased in nigral tissue. MiR-103a-3p directly repressed AGFG1 and attenuated thapsigargin-induced ER stress, while miR-103a-3p inhibition or AGFG1 overexpression exacerbated stress signalling. AGFG1 knockdown reversed the effects of miR-103a-3p inhibition, establishing AGFG1 as a functional downstream effector. Mechanistically, AGFG1 associated and co-trafficked with clathrin-positive vesicles, whereas ER stress progressively disrupted AGFG1-clathrin vesicle dynamics, revealing an association between endocytic trafficking and stress signalling. In genetic Parkinson's disease models, SNCA A53T and LRRK2 G2019S neurons showed mutation-dependent differences in AGFG1 expression and stress regulation. eIF2 phosphorylation increased in both SNCA A53T and LRRK2 G2019S neurons, whereas AGFG1 and GADD34 upregulation was selective to SNCA A53T neurons. Importantly, ASO-mediated AGFG1 suppression attenuated ER stress in vitro and preserved nigral dopaminergic neurons with improved motor performance in vivo. Conclusion: Our findings identify the miR-103a-3p/AGFG1 axis as a previously unrecognised molecular link between endocytic trafficking dysfunction and ER stress in Parkinson's disease, and support AGFG1 as a mechanistically potential therapeutic target.

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Zhang, Z. W., Chia, S.-Y., Wong, L. J., Li, Z., Tu, H., Tan, E.-K., Zhou, Z., Cao, M., Zeng, L.. 2026-10-24. Dysregulation of miR-103a-3p/AGFG1 axis links endocytic trafficking dysfunction to ER stress in Parkinson's disease. https://doi.org/10.64898/2026.10.21.760838

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