Evidence map›Paper›PMID 38296953›Full record

ArticleNPJ Parkinson's disease2024

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 and 7 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in NPJ Parkinson's disease, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.

0numbers the graph read from it
0cells of the map it votes in
18citing papers in PubMed
6.2field-weighted citation impact, top 3% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

18 citing papers in PubMed, 23 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

17 authors at 6 institutions in 2 countries.

Heng Huang *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.
Lishan Lin *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.ORCID http://orcid.org/0000-0001-5962-0712
Tengteng WuDepartment of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Cheng WuGuangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Leping ZhouDepartment of Neurology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Ge LiGuangdong Provincial Key Laboratory of Laboratory Animals, Guangdong Laboratory Animals Monitoring Institute, Guangzhou, China.
Fengjuan SuDepartment 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.
Fengyin LiangDepartment 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.
Wenyuan GuoDepartment of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Weineng ChenDepartment 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.
Qiuhong JiangDepartment 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.
Yalun GuanGuangdong Provincial Key Laboratory of Laboratory Animals, Guangdong Laboratory Animals Monitoring Institute, Guangzhou, China.
Xuejiao LiGuangdong Provincial Key Laboratory of Laboratory Animals, Guangdong Laboratory Animals Monitoring Institute, Guangzhou, China.
Pingyi XuDepartment of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.ORCID http://orcid.org/0000-0001-8716-5892
Yu ZhangGuangdong Provincial Key Laboratory of Laboratory Animals, Guangdong Laboratory Animals Monitoring Institute, Guangzhou, China.
Wanli SmithDepartment of Psychiatry, Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
Zhong PeiDepartment 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.ORCID http://orcid.org/0000-0002-7986-3452
Sun Yat-sen University · CNGuangdong Laboratory Animals Monitoring Institute · CNFirst Affiliated Hospital of Guangzhou Medical University · CNGuangdong Academy of Medical Sciences · CNJohns Hopkins University · USThird Affiliated Hospital of Guangzhou Medical University · CN

Funding

National Natural Science Foundation of China (National Science Foundation of China) 82071255National Natural Science Foundation of China (National Science Foundation of China) 82271266
6 · The paper itself

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.

Identifiers

PMID38296953
PMCPMC10831045
OpenAlexW4391387819

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.