Objective: To investigate PARP9 expression and localization in PD models, evaluate its effects on dopaminergic neuronal injury and microglial activation, and determine whether PARP9 regulates neuron–microglia mitochondrial transfer through TNTs.

Background: Parkinson’s disease (PD) is characterized by progressive loss of dopaminergic neurons in the substantia nigra. Neuroinflammation, particularly microglial activation, plays an important role in PD progression. In our previous MPTP-induced PD mouse model, dopaminergic neuronal apoptosis and microglial activation were markedly increased in the substantia nigra. PARP9 has been associated with apoptosis and neuroinflammation in brain injury, but its role in PD remains unclear. Recent studies suggest that neurons and microglia can exchange mitochondria through tunneling nanotubes (TNTs), which may contribute to PD pathology.

Method: An MPTP-induced PD mouse model and a neuron (SH-SY5Y)–microglia (HMC3) co-culture system were used. PARP9 expression and localization were assessed by immunohistochemistry, immunofluorescence, and Western blotting. AAV-mediated knockdown/overexpression and siRNA transfection were used to modulate PARP9 expression in vivo and in vitro. Neuronal apoptosis and inflammatory cytokines were evaluated by TUNEL, Western blotting, immunofluorescence, and ELISA. MitoTracker labeling, Phalloidin staining, and confocal microscopy were used to assess mitochondrial transfer, TNT formation, and mitochondrial function.

Results: MPTP-treated mice showed reduced TH-positive neurons and increased Iba1-positive microglial activation in the substantia nigra pars compacta. PARP9 expression was significantly upregulated in the midbrain substantia nigra and co-localized with TH-positive neurons and Iba1-positive microglia. PARP9 knockdown alleviated neuronal apoptosis and neuroinflammation, whereas PARP9 overexpression aggravated both processes.

Conclusion: PARP9 upregulation may disrupt TNT-mediated mitochondrial transfer between neurons and microglia, impair mitochondrial homeostasis, aggravate dopaminergic neuronal apoptosis, and promote microglial activation and inflammatory cytokine release, thereby accelerating PD progression.

« Back to 2026 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/mechanistic-study-of-parp9-mediated-mitochondrial-transfer-in-regulating-dopaminergic-neuronal-injury-and-neuroinflammation-in-parkinsons-disease/