Journal
BRAIN BEHAVIOR AND IMMUNITY
Volume 95, Issue -, Pages 310-320Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbi.2021.04.003
Keywords
ATP-sensitive potassium channel; Kir6.1; Parkinson's disease; Astrocytes; NF-kappa B; C3
Categories
Funding
- Drug Innovation Major Project [2018ZX09711001-003-007]
- National Natural Science Foundation of China [81630099]
- Natural Science Foundation of the Jiangsu Higher Education Institutions of China [19KJA310004]
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The study suggests that the astrocytic Kir6.1/K-ATP channel plays a role in preventing neurodegeneration in PD by facilitating astrocyte-neuron communication through NF-KB/C3/C3aR signaling. Targeting astroglial Kir6.1/K-ATP channel-NF-kappa B-C3-neuronal C3aR signaling could be a novel therapeutic strategy for PD.
Complement pathway over-activation has been implicated in a variety of neurological diseases. However, the signaling pathways governing astrocytic complement activation in Parkinson's disease (PD) are poorly understood. Kir6.1, a pore-forming subunit of ATP-sensitive potassium (K-ATP) channel, is prominently expressed in astrocytes and exhibits anti-inflammatory effects. Therefore, we hypothesize that Kir6.1/K-ATP channel may regulate astrocytic complement activation in the pathogenesis of PD. In this study, astrocytic Kir6.1 knockout (KO) mice were used to examine the effect of astrocytic Kir6.1/K-ATP channel on astrocytic complement activation triggered by the lipopolysaccharide (LPS). Here, we found that astrocytic Kir6.1 KO mice showed more dopaminergic neuron loss and more astmcyte reactivity in substantia nigra compacta than controls. We also found that astrocytic Kir6.1 KO increased the expression of complement C3 in astrocytes in LPS-induced mouse model of PD. Mechanistically, astrocytic Kir6.1 KO promoted astroglial NF-kappa B activation to elicit extracellular release of C3, which in turn interacted with neuronal C3aR to induce neuron death. Blocking complement function by NF-kappa B inhibitor or C3aR antagonist rescued the aggravated neuron death induced by Kir6.1 KO. Collectively, our findings reveal that astrocytic Kir6.1/K-ATP channel prevents neurodegeneration in PD via astrocyte-neuron cross talk through NF-KB/C3/C3aR signaling and suggest that targeting astmglial Kir6.1/K-ATP channel-NF-kappa B-C3-neuronal C3aR signaling represents a novel therapeutic strategy for PD.
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