Abstract
BackgroundThe first pathology observed in Parkinson’s disease (PD) is ‘dying back’ of striatal dopaminergic (DA) terminals. Connexin (Cx)30, an astrocytic gap junction protein, is upregulated in the striatum in PD, but its roles in neurodegeneration remain elusive. We investigated Cx30 function in an acute PD model by administering 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to wild-type (WT) and Cx30 knockout (KO) mice.MethodsOn days 1 and 7 after MPTP administration, we evaluated changes in astrocytic Cx30, Cx43, glial fibrillary acidic protein, and ionised calcium-binding adapter molecule 1 expression by immunostaining and biochemical analysis. Loss of DA neurons was evaluated by tyrosine hydroxylase immunostaining. Gene expression was analysed using A1, A2, pan-reactive astrocyte microarray gene sets, and M1, M2, and M1/M2 mixed microglial microarray gene sets. Real-time PCR and in situ hybridisation were performed to evaluate glial cell-derived neurotrophic factor (Gdnf) and S100a10 expression. Striatal GDNF protein levels were determined by enzyme-linked immunosorbent assay.ResultsMPTP treatment induced upregulation of Cx30 and Cx43 levels in the striatum of WT and KO mice. DA neuron loss was accelerated in Cx30 KO compared with WT mice after MPTP administration, despite no change in the striatal concentration of methyl-4-phenylpyridinium+. Astrogliosis in the striatum of Cx30 KO mice was attenuated by MPTP, whereas microglial activation was unaffected. Microarrays of the striatum showed reduced expression of pan-reactive and A2 astrocyte genes after MPTP treatment in Cx30 KO compared with WT mice, while M1, M2, and M1/M2 mixed microglial gene expression did not change. MPTP reduced the number of striatal astrocytes co-expressing Gdnf mRNA and S100β protein or S100a10 mRNA and S100β protein and also reduced the level of GDNF in the striatum of Cx30 KO compared with WT mice.ConclusionsThese findings indicate that Cx30 plays critical roles in astrocyte neuroprotection in an MPTP PD model.
Highlights
The first pathology observed in Parkinson’s disease (PD) is ‘dying back’ of striatal dopaminergic (DA) terminals
The number of Cx30 dots was significantly increased between days 1 and 7 in MPTP-treated, but not Normal saline (NS)-treated, mice (p < 0.0001, Fig. 2a), suggesting that MPTP treatment increased the expression of Cx30
We found that basal levels of glial cell-derived neurotrophic factor (Gdnf) mRNA and glial cell-derived neurotrophic factor (GDNF) protein in the striatum were similar in WT and Cx30 KO mice, but their levels were significantly lower in Cx30 KO mice than in WT mice on day 1 after MPTP treatment
Summary
The first pathology observed in Parkinson’s disease (PD) is ‘dying back’ of striatal dopaminergic (DA) terminals. Parkinson’s disease (PD) is a common neurological disorder characterised by progressive degeneration of dopaminergic (DA) neurons and the formation of cytoplasmic inclusions called Lewy bodies in the substantia nigra pars compacta (SNc). Accumulating evidence suggests important roles for non-neuronal cells, especially astrocytes, in DA neuron degeneration [2]. Astrocytes are the most abundant glial cell type in the central nervous system and play crucial roles in brain homeostasis, providing metabolic, electrical, and structural support for surrounding neurons in both normal and pathological conditions [3]. Astrocytes undergo a dynamic transformation called reactive astrogliosis. The functions of reactive astrocytes are controversial, and they have been reported to play both neuroprotective and neurodegenerative roles, providing another example of their heterogeneity [5]. It has been proposed that two types of reactive astrocytes, harmful A1 and protective A2 types, should be recognised based on genetic classification [6, 7]
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