TAB2 Causes Neuronal Damage by Aggravating Microglia-Mediated Neuroinflammation in Parkinson's Disease.
TAB2 Causes Neuronal Damage by Aggravating Microglia-Mediated Neuroinflammation in Parkinson's Disease.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Beijing, CN · Author affiliation
Department of Functional Neurosurgery, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.Location evidence
Jinan, CN · Author affiliation
Department of Neurosurgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.Location evidence
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Original abstract
Neuroinflammation plays a key role in exacerbating dopaminergic neuron loss in Parkinson's disease (PD). We identified TAB2 as an early-stage biomarker, which was elevated in PD patients' microglia. However, the role of TAB2 in the pathogenesis of PD remains unknown. In this study, we found that Tab2 knockdown inhibited the activation of microglia and protected neurons in PD models. STAT3, as a transcription factor for TAB2, regulated TAB2 expression. Mechanistically, TAB2 interacted with α-synuclein and facilitated the recognition of K63-linked ubiquitin chains, leading to the formation of the TAK1-TABs complex and activation of TAK1, which was ultimately followed by activation of the nuclear factor-kappa B (NF-κB) signaling pathway. Furthermore, microglia-specific knockdown of Tab2 significantly inhibited microglia activation, protected dopaminergic neurons, improved motor function, and attenuated anxiety-like behaviors in PD mouse model. We further showed that the FDA-approved drug, lumacaftor, suppressed microglial TAB2 expression and had potent anti-inflammatory and neuroprotective effects in PD models. Taken together, our study reveals that the STAT3-TAB2-NF-κB-IL-1β positive feedback axis in microglia is a crucial checkpoint that exacerbates neuroinflammation in PD. Therefore, these findings identify a pivotal role of TAB2 in regulating microglia-mediated neuroinflammation, suggesting that targeting TAB2 may be a possible therapeutic strategy for PD.