JWA binding to NCOA4 alleviates degeneration in dopaminergic neurons through suppression of ferritinophagy in Parkinson's disease
Xinxin Zhao,
Zhengwei Kang,
Ruixue Han,
Min Wang,
Yueping Wang,
Xin Sun,
Cong Wang,
Jianwei Zhou,
Lei Cao,
Ming Lu
Affiliations
Xinxin Zhao
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing 211166, China
Zhengwei Kang
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing 211166, China
Ruixue Han
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing 211166, China
Min Wang
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing 211166, China
Yueping Wang
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing 211166, China
Xin Sun
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing 211166, China
Cong Wang
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing 211166, China
Jianwei Zhou
Department of Molecular Cell Biology & Toxicology, Center for Global Health, School of Public Health, Nanjing Medical University, 211166, Nanjing, China; Changzhou Second People's Hospital, Changzhou Medical Center, Nanjing Medical University, 213000, Changzhou, China
Lei Cao
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing 211166, China; Changzhou Second People's Hospital, Changzhou Medical Center, Nanjing Medical University, 213000, Changzhou, China; Corresponding author. Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, 211166, China.
Ming Lu
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing 211166, China; Changzhou Second People's Hospital, Changzhou Medical Center, Nanjing Medical University, 213000, Changzhou, China; Corresponding author. Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 211166, Nanjing, China.
Parkinson's disease (PD) poses a significant challenge in neurodegenerative disorders, characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). The intricate mechanisms orchestrating DA neurodegeneration in PD are not fully understood, necessitating the exploration of innovative therapeutic approaches. Recent studies have implicated ferroptosis as a major contributor to the loss of DA neurons, revealing a complex interplay between iron accumulation and neurodegeneration. However, the sophisticated nature of this process challenges the conventional belief that mere iron removal could effectively prevent DA neuronal ferroptosis. Here, we report JWA, alternatively referred to as ARL6IP5, as a negative regulator of ferroptosis, capable of ameliorating DA neuronal loss in the context of PD. In this study, synchronized expression patterns of JWA and tyrosine hydroxylase (TH) in PD patients and mice were observed, underscoring the importance of JWA for DA neuronal survival. Screening of ferroptosis-related genes unraveled the engagement of iron metabolism in the JWA-dependent inhibition of DA neuronal ferroptosis. Genetic manipulation of JWA provided compelling evidence linking its neuroprotective effects to the attenuation of NCOA4-mediated ferritinophagy. Molecular docking, co-immunoprecipitation, and immunofluorescence studies confirmed that JWA mitigated DA neuronal ferroptosis by occupying the ferritin binding site of NCOA4. Moreover, the JWA-activating compound, JAC4, demonstrated promising neuroprotective effects in cellular and animal PD models by elevating JWA expression, offering a potential avenue for neuroprotection in PD. Collectively, our work establishes JWA as a novel regulator of ferritinophagy, presenting a promising therapeutic target for addressing DA neuronal ferroptosis in PD.
