Knock-out of the critical nitric oxide synthase regulator DDAH1 in mice impacts amphetamine sensitivity and dopamine metabolism

Kozlova, Alena A.; Rubets, Elena; Vareltzoglou, Magdalini R.; Jarzebska, Natalia; Ragavan, Vinitha N.; Chen, Yingjie; Martens‐Lobenhoffer, Jens; Bode‐Böger, Stefanie M.; Gainetdinov, Raul R.; Rodionov, Roman N.; Bernhardt, Nadine

doi:10.1007/s00702-023-02597-7

Cited by 5 publications

(2 citation statements)

References 109 publications

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“…The DDAH-1 deletion in WT rats did not influence on locomotor activity and muscle strength, consistent with that in DDAH-1 KO mouse constructed by a fourth-exon deletion. These KO mice exhibited unaltered general locomotor activity while reduced sensitivity to amphetamine indicating impaired dopamine system [35]. In our study, DDAH-1 deletion exacerbated impaired locomotor function and dopaminergic neurodegeneration in PD rats.…”

Section: Discussionsupporting

confidence: 51%

“…It did not additionally induce other cellular damages under a relatively modest concentration of ROT. Moreover, Kozlova et al suggested DDAH-1 influenced animal behavior and the dopamine system, most probably via the NO pathway [35]. However, the study lacked experimental evidence for the impact of DDAH-1 loss on the brain or specific region changes in NO levels.…”

Section: Discussionmentioning

confidence: 96%

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DDAH-1 maintains endoplasmic reticulum-mitochondria contacts and protects dopaminergic neurons in Parkinson’s disease

Zhao,

Shen,

Zhang

et al. 2024

Cell Death Dis

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The loss of dopaminergic neurons in the substantia nigra is a hallmark of pathology in Parkinson’s disease (PD). Dimethylarginine dimethylaminohydrolase-1 (DDAH-1) is the critical enzyme responsible for the degradation of asymmetric dimethylarginine (ADMA) which inhibits nitric oxide (NO) synthase and has been implicated in neurodegeneration. Mitochondrial dysfunction, particularly in the mitochondria-associated endoplasmic reticulum membrane (MAM), plays a critical role in this process, although the specific molecular target has not yet been determined. This study aims to examine the involvement of DDAH-1 in the nigrostriatal dopaminergic pathway and PD pathogenesis. The distribution of DDAH-1 in the brain and its colocalization with dopaminergic neurons were observed. The loss of dopaminergic neurons and aggravated locomotor disability after rotenone (ROT) injection were showed in the DDAH-1 knockout rat. l-arginine (ARG) and NO donors were employed to elucidate the role of NO respectively. In vitro, we investigated the effects of DDAH-1 knockdown or overexpression on cell viability and mitochondrial functions, as well as modulation of ADMA/NO levels using ADMA or ARG. MAM formation was assessed by the Mitofusin2 oligomerization and the mitochondrial ubiquitin ligase (MITOL) phosphorylation. We found that DDAH-1 downregulation resulted in enhanced cell death and mitochondrial dysfunctions, accompanied by elevated ADMA and reduced NO levels. However, the recovered NO level after the ARG supplement failed to exhibit a protective effect on mitochondrial functions and partially restored cell viability. DDAH-1 overexpression prevented ROT toxicity, while ADMA treatment attenuated these protective effects. The declines of MAM formation in ROT-treated cells were exacerbated by DDAH-1 downregulation via reduced MITOL phosphorylation, which was reversed by DDAH-1 overexpression. Together, the abundant expression of DDAH-1 in nigral dopaminergic neurons may exert neuroprotective effects by maintaining MAM formation and mitochondrial function probably via ADMA, indicating the therapeutic potential of targeting DDAH-1 for PD.

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Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 96%

DDAH-1 maintains endoplasmic reticulum-mitochondria contacts and protects dopaminergic neurons in Parkinson’s disease

Zhao,

Shen,

Zhang

et al. 2024

Cell Death Dis

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The emerging role of dimethylarginine dimethylaminohydrolase 2 in regulating vasculogenic mimicry in cancer

Mangoni,

Weerakoon,

Ragavan

et al. 2025

Therapeutic Applications of Nitric Oxide in Cancer and Inflammatory Disorders

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Molecular Dynamics-Ensemble Docking and Biophysical Studies for Structure-Based Identification of Non-Amino Acidic Ligands of DDAH-1

Bigiotti,

Bianconi,

Ruta

et al. 2024

J. Chem. Inf. Model.

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Dimethylarginine dimethylaminohydrolase-1 (DDAH-1) accounts for the catabolism of the endogenous inhibitors of nitric oxide (NO) synthases, namely, ADMA (N ω ,N ω -dimethyl-L-arginine) and NMMA (N ω -monomethyl-L-arginine). Inhibition of DDAH-1 may prove a therapeutic benefit in diseases associated with elevated nitric oxide (NO) levels by providing a tissue-specific increase of ADMA and NMMA. In this work, we have used molecular dynamics to generate a pool of DDAH-1 conformations in the apo and holo forms. Ensemble docking has been instrumental in screening an in-house fragment-based library of 824 compounds. Resulting virtual hits have been validated for their binding activity to recombinant human DDAH-1 using microscale thermophoresis (MST). As a key result, three non-amino acidic ligands of DDAH-1 (VIS212, VIS268, VIS726) are identified with higher binding efficiency index than ADMA. Amid these compounds, purpurogallin (VIS726) proves a potent ligand of DDAH-1, showing a mixed behavior of enzymatic inhibition in a biochemical assay. This finding widens the panel of known molecular targets of purpurogallin and provides clues into the molecular mechanisms of its cellular NO inhibition activity as well as its anti-inflammatory and neuroprotective effects.

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Knock-out of the critical nitric oxide synthase regulator DDAH1 in mice impacts amphetamine sensitivity and dopamine metabolism

Cited by 5 publications

References 109 publications

DDAH-1 maintains endoplasmic reticulum-mitochondria contacts and protects dopaminergic neurons in Parkinson’s disease

DDAH-1 maintains endoplasmic reticulum-mitochondria contacts and protects dopaminergic neurons in Parkinson’s disease

The emerging role of dimethylarginine dimethylaminohydrolase 2 in regulating vasculogenic mimicry in cancer

Molecular Dynamics-Ensemble Docking and Biophysical Studies for Structure-Based Identification of Non-Amino Acidic Ligands of DDAH-1

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