Phosphorylation of AQP4 by LRRK2 R1441G impairs glymphatic clearance of IFNγ and aggravates dopaminergic neurodegeneration

Heng Huang; Lishan Lin; Tengteng Wu; Cheng Wu; Leping Zhou; Ge Li; Fengjuan Su; Fengyin Liang; Wenyuan Guo; Weineng Chen; Qiuhong Jiang; Yalun Guan; Xuejiao Li; Pingyi Xu; Yu Zhang; Wanli Smith; Zhong Pei

doi:10.1038/s41531-024-00643-z

Phosphorylation of AQP4 by LRRK2 R1441G impairs glymphatic clearance of IFNγ and aggravates dopaminergic neurodegeneration

NPJ Parkinsons Dis. 2024 Jan 31;10(1):31. doi: 10.1038/s41531-024-00643-z.

Authors

Heng Huang^#¹, Lishan Lin^#¹, Tengteng Wu², Cheng Wu³, Leping Zhou⁴, Ge Li⁵, Fengjuan Su¹, Fengyin Liang¹, Wenyuan Guo², Weineng Chen¹, Qiuhong Jiang¹, Yalun Guan⁵, Xuejiao Li⁵, Pingyi Xu², Yu Zhang⁵, Wanli Smith⁶, Zhong Pei⁷

Affiliations

¹ Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Guangzhou, China.
² Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
³ Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
⁴ Department of Neurology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
⁵ Guangdong Provincial Key Laboratory of Laboratory Animals, Guangdong Laboratory Animals Monitoring Institute, Guangzhou, China.
⁶ Department of Psychiatry, Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
⁷ Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Guangzhou, China. peizhong@mail.sysu.edu.cn.

^# Contributed equally.

Abstract

Aquaporin-4 (AQP4) is essential for normal functioning of the brain's glymphatic system. Impaired glymphatic function is associated with neuroinflammation. Recent clinical evidence suggests the involvement of glymphatic dysfunction in LRRK2-associated Parkinson's disease (PD); however, the precise mechanism remains unclear. The pro-inflammatory cytokine interferon (IFN) γ interacts with LRRK2 to induce neuroinflammation. Therefore, we examined the AQP4-dependent glymphatic system's role in IFNγ-mediated neuroinflammation in LRRK2-associated PD. We found that LRRK2 interacts with and phosphorylates AQP4 in vitro and in vivo. AQP4 phosphorylation by LRRK2 R1441G induced AQP4 depolarization and disrupted glymphatic IFNγ clearance. Exogeneous IFNγ significantly increased astrocyte expression of IFNγ receptor, amplified AQP4 depolarization, and exacerbated neuroinflammation in R1441G transgenic mice. Conversely, inhibiting LRRK2 restored AQP4 polarity, improved glymphatic function, and reduced IFNγ-mediated neuroinflammation and dopaminergic neurodegeneration. Our findings establish a link between LRRK2-mediated AQP4 phosphorylation and IFNγ-mediated neuroinflammation in LRRK2-associated PD, guiding the development of LRRK2 targeting therapy.

Abstract

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