2. Academic Validation
  3. 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

  • Cell Death Dis. 2024 Jun 7;15(6):399. doi: 10.1038/s41419-024-06772-w.
Yichen Zhao # 1,  Weiwei Shen # 2,  Minjie Zhang # 1,  Min Guo 2,  Yunxiao Dou 1,  Sida Han 2,  Jintai Yu 3,  Mei Cui 4,  Yanxin Zhao 5
Affiliations

Affiliations

  • 1 Department of Neurology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
  • 2 Department of Neurology and Institute of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
  • 3 Department of Neurology, Huashan Hospital, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China. jintai_yu@fudan.edu.cn.
  • 4 Department of Neurology and Institute of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China. cuimei@fudan.edu.cn.
  • 5 Department of Neurology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China. zhao_yanxin@tongji.edu.cn.
  • # Contributed equally.
PMID: 38849335 DOI: 10.1038/s41419-024-06772-w
Abstract

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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