TRX/TXNIP/miRs network in neuronal cells and TXNIP-targeted miRs modulate neuroinflammation, neuronal apoptosis, and mitochondrial dysfunction in Parkinson's disease: A review.

The purpose of this review is to explore the role of the thioredoxin (TRX)/TRX-interacting protein (TXNIP)/microRNAs (miRs) network in neuronal cells and the function of TXNIP-targeted miRs in regulating neuroinflammation, neuronal apoptosis, and mitochondria dysfunction in Parkinson's disease (PD). The high TXNIP level activates apoptosis signal-regulating kinase-1 (ASK-1) and trigger a signaling cascade involving the phosphorylation of c-Jun-N-terminal kinase (JNK) and mitogen-activated protein kinase (p38 MAPK). The activation of these kinases contributes to the misfolding and aggregation of α-synuclein, a hallmark of PD. The brain's TXNIP level in response to oxidative stress is supported by miRs. In PD, miRs such as miR-17, miR-20a, and miR-106b are typically downregulated, resulting in elevated TXNIP levels and the subsequent exacerbation of neuroinflammation. Activation of the Nrf2-ARE (nuclear factor erythroid 2-related factor 2-antioxidant response element) pathway enhances cellular resistance to oxidative stress by upregulating antioxidant genes, including those encoding miRs that inhibit TXNIP. MiR therapy faces several challenges in clinical application, such as the optimization of delivery systems, potential off-target effects, and the achievement of precise treatment. Exploring these bottlenecks and countermeasures can help readers gain a comprehensive understanding of the current research status and future development direction in this field.