title: Aquaporin-4 deficiency diminishes the differential degeneration of midbrain dopaminergic neurons in experimental Parkinson's disease.
abstract: Parkinson's disease (PD) is primarily due to the progressive, selective and irreversible loss of dopaminergic (DA) neurons in the substantia nigra (SN). Interestingly, DA neurons in the ventral and lateral SN are much more susceptible than adjacent dopamine neurons in the ventral tegmental area (VTA) not only in human PD but in many PD model systems. However, the molecular causes of regional vulnerability in PD remain unknown. In our previous studies, we established acute PD animal models by administration of MPTP (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine), and found that AQP4 knockout mice were significantly more prone to MPTP-induced neurotoxicity. Here, we further observe that AQP4 deficiency resulted in the same susceptible to MPTP between SN DA neuron and VTA neurons both in acute and chronic PD model. Moreover, we show that AQP4 deficiency increased the numbers of reactive astrocytes and microglias not only in the SN and but also in the VTA under basal and MPTP-induced situations. Meanwhile, AQP4 deficiency disrupted the balance of the pro-inflammatory cytokine/neurotrophin in midbrain. Taken together, these results demonstrate that glial AQP4 is involved in the susceptibility differences of DA neurons between SN and VTA, although the precise mechanism of AQP4 remains to be explored. Moreover, these findings also suggest that these susceptibility differences are not only due to intrinsic neuronal factors, but also attribute to differences in astrocytes of these regions.
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China; Division of Clinical Pharmacy, Department of Pharmacy, the First AffiliaMACted Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Ji
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Beibei
authors.initials: B
authors.lastname: Yang
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Sun
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Mengdi
authors.initials: M
authors.lastname: Liu
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Ding
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Fang
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China. Electronic address: Yfan@njmu.edu.cn.
authors.forename: Yi
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Hu
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000208:Acute Disease; D000818:Animals; D051401:Aquaporin 4 / Q000235:genetics*; D001253:Astrocytes / Q000473:pathology; D002908:Chronic Disease; D059290:Dopaminergic Neurons / Q000473:pathology*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D018345:Mice, Knockout; D009410:Nerve Degeneration; D009457:Neuroglia / Q000473:pathology; D010300:Parkinson Disease / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D013378:Substantia Nigra / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000473:pathology
chemical_list: D051401:Aquaporin 4; D051100:Glial Cell Line-Derived Neurotrophic Factor; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D016222:Fibroblast Growth Factor 2; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
keywords: Aquaporin 4; Astrocyte; Dopamine; Neurodegeneration; Parkinson’s disease