Aberrant Tonic Inhibition of Dopaminergic Neuronal Activity Causes Motor Symptoms in Animal Models of Parkinson’s Disease

Heo, Jun Young; Nam, Min; Yoon, Hyun Soo; Kim, Jeong-Yeon; Hwang, Yu Jin; Won, Woojin; Woo, Dong Ho; Lee, Ji Ae; Park, Hyun Jung; Jo, Seonmi; Lee, Min Joung; Kim, Sunpil; Shim, Jeong Eun; Jang, Dong Pyo; Kim, Kyoung I.; Huh, Sue H.; Jeong, Jae Yeong; Kowall, Neil W.; Lee, Jung‐Hee; Im, Hyeonjoo; Park, Jong Hyun; Jang, Bo Ko; Park, Ki Duk; Lee, Hyunjoo Jenny; Shin, Hyogeun; Cho, Il‐Joo; Hwang, Eun Mi; Kim, Young Soo; Kim, Hye Yun; Oh, Soo Jin; Lee, Seung Eun; Paek, Sun Ha; Yoon, Jong Hyuk; Jin, Byung Kwan; Kweon, Gi Ryang; Shim, Insop; Hwang, Onyou; Ryu, Hoon; Jeon, Sang Ryong; Lee, C. Justin

doi:10.1016/j.cub.2019.11.079

Cited by 78 publications

(105 citation statements)

References 67 publications

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“…Therefore, MAO-B has been believed to degrade dopamine which is a monoamine neurotransmitter and MAO-B inhibitors have been believed to exert anti-Parkinsonian effects by blocking the degradation of dopamine (Schapira, 2011). In contrast, recent studies have demonstrated that MAO-B expression is dramatically increased in reactive astrocytes and that MAO-B is responsible for astrocytic GABA synthesis through the putrescine degradation pathway (Heo et al, 2020;Jo et al, 2014;Nam et al, 2020;Yoon et al, 2014a). A recent study revealed that MAO-B-mediated astrocytic GABA is critically involved in the pathology of PD.…”

Section: Introductionmentioning

confidence: 94%

KDS2010, a newly developed reversible MAO-B inhibitor, as an effective therapeutic candidate for Parkinson’s disease

Nam

Park

Song

et al. 2020

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AbstractBackground and PurposeMonoamine oxidase-B (MAO-B) is a long-standing therapeutic target for Parkinson’s disease (PD), however, previous clinical studies demonstrated discouraging effects of currently available irreversible MAO-B inhibitors. Since KDS2010, a novel, potent, selective, and reversible MAO-B inhibitor, has been developed, here we tested its therapeutic potential in animal models of PD.Experimental ApproachWe designed and synthesized α-aminoamide derivatives and compared the specificity to MAO-B and reversibility of each compound with KDS2010. To investigate the in vivo therapeutic effect, we used MPTP mouse model with two different regimes of 3-day administration (pre-treatment or post-treatment) and 30-day administration. We assessed the therapeutic potential using behavioral and immunohistochemical analyses. Additionally, the functional recovery by KDS2010 was tested in 6-hydroxydopamine-induced and A53T-alpha-synuclein overexpression models. Lastly, to validate the potential as a clinical drug candidate, we investigated the pharmacokinetics and toxicity of KDS2010 in non-human primates.Key ResultsKDS2010 showed the highest potency, specificity, and reversibility among the α-aminoamide derivatives, with high bioavailability (>100%) and BBB permeability. KDS2010 also showed significant neuroprotective and anti-neuroinflammatory effects in the nigrostriatal pathway, leading to an alleviation of MPTP-induced parkinsonism in all administration regimes. In particular, the therapeutic effect of KDS2010 was superior to selegiline, an irreversible MAO-B inhibitor. KDS2010 also showed a potent therapeutic effect in 6-hydroxydopamine and A53T models. Moreover, KDS2010 showed virtually no toxicity or side-effect in non-human primates.Conclusion and ImplicationsKDS2010 shows excellent therapeutic potential and safety in various PD animal models. KDS2010, therefore, could be a next-generation therapeutic candidate for PD.Representative SchematicWhat is already knownKDS2010 is a recently developed potent, selective, and reversible MAO-B inhibitor.MAO-B is critical for PD pathology through astrocytic GABA and H2O2 synthesis.What this study addsKDS2010 treatment dramatically recovers from PD-related pathology and motor deficit after pre- and post-treatment regimes in several animal models of PD.KDS2010 exhibits low toxicity and excellent pharmacokinetic profile in non-human primates.What is the clinical significance?KDS2010 is a safe and promising therapeutic candidate for Parkinson’s disease.Reversible MAO-B inhibitors could be more effective for treatment of Parkinson’s disease, overcoming the short-lived actions of irreversible MAO-B inhibitors.

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Section: Introductionmentioning

confidence: 94%

KDS2010, a newly developed reversible MAO-B inhibitor, as an effective therapeutic candidate for Parkinson’s disease

Nam

Park

Song

et al. 2020

Preprint

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“…Viral injection of AAV-A53T-SNCA is reported to induce significant parkinsonian motor deficits in rodents with a significant decrease in TH levels, the key dopamine-synthesizing enzyme, within 3 to 4 weeks. 18 Therefore, to evaluate the expression level of the SNCA protein, we performed immunohistochemistry with an antibody against α -synuclein in the fourth week after virus injection. As a prerequisite, we confirmed by immunohistochemistry using an HA tag that the CRISPR protein was properly expressed in ipsilateral SNpc.…”

Section: Aav-crispr-a53t Prevents α -Synuclein Overexpression and Th mentioning

confidence: 99%

“…We further investigated whether gene editing of A53T-SNCA prevents A53T-SNCA overexpression-induced parkinsonian motor symptoms in vivo ( Figure 5A). To assess the PDlike motor symptoms, we performed a stepping test, which has been validated in previous studies, 18,33 during the second, third, and fourth week after virus injection. As expected, there was no significant difference in the stepping numbers of ipsilateral forelimbs between the groups.…”

Section: Aav-crispr-a53t Prevents α -Synuclein Overexpression-inducedmentioning

confidence: 99%

“…In the present study, we virally overexpressed A53T-SNCA in the substantia nigra pars compacta (SNpc), which has been well documented to exhibit not only nigrostriatal TH loss but also α -synuclein aggregation and progressive dopaminergic (DAergic) neuronal degeneration within a few weeks, leading to parkinsonian motor deficits. [16][17][18] In 2013, Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) was first introduced as a tool for gene therapy in mammalian cells. 19,20 Despite accumulated evidence of its potential therapeutic effects in vitro, the lack of an adequate delivery method has hindered the development of gene therapy using CRISPR.…”

Section: Introductionmentioning

confidence: 99%

“…We further tested the therapeutic effect of this strategy in PD motor symptoms in an animal model of PD with virally overexpressed A53T-SNCA (A53T rat model). 18 The CRISPR-mediated A53T-SNCA gene deletion caused a significant prevention of dopaminergic neuronal loss and a dramatic behavioral recovery.…”

Section: Introductionmentioning

confidence: 99%

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CRISPR/Cas9-mediated gene editing induces neurological recovery in an A53T-SNCA overexpression rat model of Parkinson’s disease

Yoon

Lim

et al. 2020

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To date, no publicly available disease-modifying therapy for Parkinson’s disease has been developed. This can be partly attributed to the absence of techniques for in vivo deletion of the SNCA gene (encoding α-synuclein), which is one of the key players in Parkinson’s disease pathology. In particular, A53T-mutated SNCA (A53T-SNCA) is one of the most studied familial pathologic mutations in Parkinson’s disease. Here we utilized a recently discovered genome editing technique, CRISPR/Cas9, to delete A53T-SNCA in vitro and in vivo. Among various CRISPR/Cas9 systems, SaCas9-KKH with a single guide RNA (sgRNA) targeting A53T-SNCA was packaged into adeno-associated virus. Adeno-associated virus carrying SaCas9-KKH significantly reduced A53T-SNCA levels in A53T-SNCA-overexpressed HEK293T cells, without off-target effects on wild-type SNCA. Furthermore, we tested the technique’s in vivo therapeutic potential in a viral A53T-SNCA overexpression rat model of Parkinson’s disease. Gene deletion of A53T-SNCA significantly prevented the overexpression of α-synuclein, dopaminergic neurodegeneration, and parkinsonian motor symptoms, whereas a negative control without sgRNA did not. Our findings propose CRISPR/Cas9 system as a potential therapeutic tool for A53T-SNCA familial Parkinson’s disease.

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Diagnostic and therapeutic potential of tonic gamma‐aminobutyric acid from reactive astrocytes in brain diseases

Koh,

Lee

2024

Clinical & Translational Med

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Diagnostic and therapeutic potential of tonic gamma-aminobutyric acid from reactive astrocytes in brain diseasesDear Editor, Gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the brain, serves as a cornerstone in modulating neuronal activity and maintaining cognitive functions. Its role extends beyond fast-acting phasic inhibition, as slow-acting tonic GABA inhibition, mediated by extrasynaptic GABA A receptors, responds to ambient GABA levels (i.e. GABA tone), significantly influencing synaptic plasticity, learning and memory, and sensory processing. 1 Dysregulation of tonic GABA inhibition in a range of neurological and psychiatric diseases is associated with cognitive decline, motor symptoms, and other functional impairments, highlighting the potentially broad impact of GABA tone across various diseases. One of the common cellular responses in pathological conditions is the emergence of reactive astrocytes, 2 often accompanied by upregulation of monoamine oxidase B (MAO-B) expression and increased GABA synthesis (Figure 1A), thus affecting neighbouring neurons through tonic inhibition. 3 Here, we present the impact of pathological GABA tone and propose its therapeutic and diagnostic targets for clinical applications.Astrocytes once thought to be mere support cells, emerge as key players in the regulation of GABA tone through various mechanisms of GABA synthesis, release, and clearance. 1 These cells are strategically positioned to interface closely with neurons, allowing them to effectively regulate GABA tone in the extrasynaptic space. This role becomes particularly crucial in a range of pathological conditions, such as Alzheimer's 3-5 and Parkinson's diseases. 6,7 In these conditions, astrocytes become reactive, exhibiting increased MAO-B expression and enhanced GABA synthesis, which contributes to an elevated GABA tone and leads to pathological symptoms. This phenomenon is not limited to Alzheimer's and Parkinson's disease but is also observed in stroke, 8 depression, 9 obesity, 10 and potentially extends to conditions like post-traumatic stress disorderThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Aberrant Tonic Inhibition of Dopaminergic Neuronal Activity Causes Motor Symptoms in Animal Models of Parkinson’s Disease

Abstract: Highlights d Reactive astrocytes in SNpc produce excessive GABA via MAO-B in animal models of PD d Aberrant tonic inhibition causes reduced DA production in neurons and motor deficits d Dormant neurons are rescued by MAO-B inhibition or optogenetic neuronal activation

Cited by 78 publications

References 67 publications

KDS2010, a newly developed reversible MAO-B inhibitor, as an effective therapeutic candidate for Parkinson’s disease

KDS2010, a newly developed reversible MAO-B inhibitor, as an effective therapeutic candidate for Parkinson’s disease

CRISPR/Cas9-mediated gene editing induces neurological recovery in an A53T-SNCA overexpression rat model of Parkinson’s disease

Diagnostic and therapeutic potential of tonic gamma‐aminobutyric acid from reactive astrocytes in brain diseases

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