The Pathological Role of Astrocytic MAOB in Parkinsonism Revealed by Genetic Ablation and Over-expression of MAOB

Abstract

The cause of Parkinson’s disease has been traditionally believed to be the dopaminergic neuronal death in the substantia nigra pars compacta (SNpc). This traditional view has been recently challenged by the proposal that reactive astrocytes serve as key players in the pathology of Parkinson’s disease through excessive GABA release. This aberrant astrocytic GABA is synthesized by the enzymatic action of monoamine oxidase B (MAOB), whose pharmacological inhibition and gene-silencing are reported to significantly alleviate parkinsonian motor symptoms in animal models of Parkinson’s disease. However, whether genetic ablation and over-expression of MAOB can bidirectionally regulate parkinsonian motor symptoms has not been tested. Here we demonstrate that genetic ablation of MAOB blocks the MPTP-induced augmentation of astrocytic GABA-mediated tonic inhibition of neighboring dopaminergic neurons as well as parkinsonian motor symptoms, indicating the necessity of MAOB for parkinsonian motor symptoms. Furthermore, we demonstrate that GFAP-MAOB transgenic mice, in which MAOB is over-expressed under the GFAP promoter for astrocyte-specific over-expression, display exacerbated MPTP-induced tonic inhibition and parkinsonian motor symptoms compared to wild-type mice, indicating the importance of astrocytic MAOB for parkinsonian motor symptoms. Our study provides genetic pieces of evidence for the causal link between the pathological role of astrocytic MAOB-dependent tonic GABA synthesis and parkinsonian motor symptoms.

Adenovirus-induced Reactive Astrogliosis Exacerbates the Pathology of Parkinson’s Disease

“…We also previously demonstrated that reactive astrocytes excessively express both GFAP and GABA in the SNpc of PD animal models, while normal astrocytes do not [ 11 ]. GFAP and GABA have also been well documented as prominent markers for reactive astrocytes in various brain regions [ 12 , 15 , 16 , 20 , 23 - 25 ]. Therefore, we investigated if the severe PD-like symptoms of the A53T+Adeno group are associated with reactive astrogliosis by performing immunofluorescence staining with antibodies against TH, GFAP, and GABA.…”

“…The astrocytic GABA has been reported to tonically inhibit neighboring dopaminergic neurons in SNpc, leading to TH loss, dopamine deficiency, and parkinsonian motor deficits [ 11 ]. The excessive GABA from reactive astrocytes has been implicated in various brain diseases accompanying neuroinflammation, including Alzheimer’s disease, stroke, epilepsy, and inflammatory cytokine-induced anxiety [ 12 , 15 , 16 , 20 , 23 - 25 ]. In all these disease conditions, the excessive astrocytic GABA tonically inhibits the neighboring neurons leading to the relevant functional deficits.…”

“…Recently, accumulating lines of evidence have suggested the critical role of astrocytes in the pathology of PD [ 6 - 12 ]. Reactive astrocytes, which are observed in the SNpc of both PD patients and animal models, aberrantly synthesize and release GABA, leading to dopaminergic neuronal dysfunction [ 11 , 12 ]. Moreover, reactive astrocytes have been reported to directly cause neuronal death via H 2 O 2 [ 13 ] and lipocalin-2 [ 14 ].…”

The Associations between COMT and MAO-B Genetic Variants with Negative Symptoms in Patients with Schizophrenia

“…Dopaminergic neurons in the substantia nigra are surrounded by astrocytes containing high levels of MAO-B [37]. In the mice model of Parkinson's disease, MAO-B overexpression in astrocytes exacerbated Parkinsonian motor dysfunction, in comparison to wild-type mice [38]. In addition, MAO-B, while less abundant than MAO-A, is also present in dopaminergic neurons of the substantia nigra, where cytosolic dopamine competes between vesicular monoamine transporters and MAO-B [39].…”

Differential Proximity of Perisynaptic Astrocytic Best1 at the Excitatory and Inhibitory Tripartite Synapses in APP/PS1 and MAOB-KO Mice Revealed by Lattice Structured Illumination Microscopy

“…The hippocampal astrocytes in APP/PS1 transgenic mice contain abundant amount of cytosolic GABA due to the high expression level and enzymatic activity of MAOB which is the main astrocytic GABA-synthetic enzyme [ 8 , 15 - 17 ]. On the other hand, the hippocampal astrocytes of the MAOB-KO mice can barely synthesize GABA due to the deficiency of MAOB [ 17 , 18 ]. To investigate the Best1 distribution at the ultrastructural resolution in these mice, we adopted a cutting-edge microscopic technique, Lattice Structured Illumination Microscopy (SIM) which yields a super optical resolution of ~120 nm [ 19 ].…”