Journal of advanced research · 2026
Sleep deprivation accelerates Parkinson's disease pathology by upregulating LAG3 in astrocytes and disrupting glymphatic system function.
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Sun Yan-Rui, Lv Qian-Kun, Xue Xin-Yu, Zhang Ying, Shi Ling-Ying, Sun Mi-le, Shen Yun, Mao Cheng-Jie, Wang Lin-Hui, Wang Fen, Liu Jun-Yi, Liu Chun-Feng
Аннотация
INTRODUCTION: Parkinson's disease (PD) progression is strongly associated with sleep disturbances, but the molecular mechanisms linking sleep loss to PD pathology remain poorly understood. Emerging evidence implicates impaired glymphatic clearance of pathological α-synuclein (α-syn) as a key factor, though how sleep deprivation disrupts this process is unclear.
OBJECTIVES: This study aimed to determine whether sleep deprivation exacerbates PD pathology by modulating lymphocyte-activation gene 3 (LAG3) expression in astrocytes, thereby impairing glymphatic system function and promoting α-syn accumulation.
METHODS: We injected α-syn preformed fibrils (PFF) into the striatum of A53T transgenic mice and subjected them to sleep deprivation. Glymphatic function was assessed using in vivo magnetic resonance imaging and fluorescent tracer-based clearance assays. Astrocytic LAG3 expression was evaluated by transcriptomic sequencing and validated by immunostaining and qPCR. Adeno-associated virus-mediated LAG3 knockdown in astrocytes was used to test causality.
RESULTS: Sleep deprivation significantly worsened motor deficits, dopaminergic neuron loss, and α-syn pathology in PD mice. It induced astrocyte reactivity and disrupted aquaporin-4 (AQP4) polarization, leading to impaired cerebrospinal fluid influx and reduced α-syn clearance. LAG3 was selectively upregulated in astrocytes under sleep-deprived conditions and promoted α-syn PFF internalization. Knockdown of astrocytic LAG3 restored AQP4 polarization, improved glymphatic clearance, and attenuated neurodegeneration and behavioral deficits.
CONCLUSION: Our findings identify astrocytic LAG3 as a critical mediator linking sleep deprivation to glymphatic dysfunction and PD progression. Targeting LAG3 may represent a promising, albeit early-stage, therapeutic strategy to mitigate α-syn pathology in PD patients with sleep disorders.
OBJECTIVES: This study aimed to determine whether sleep deprivation exacerbates PD pathology by modulating lymphocyte-activation gene 3 (LAG3) expression in astrocytes, thereby impairing glymphatic system function and promoting α-syn accumulation.
METHODS: We injected α-syn preformed fibrils (PFF) into the striatum of A53T transgenic mice and subjected them to sleep deprivation. Glymphatic function was assessed using in vivo magnetic resonance imaging and fluorescent tracer-based clearance assays. Astrocytic LAG3 expression was evaluated by transcriptomic sequencing and validated by immunostaining and qPCR. Adeno-associated virus-mediated LAG3 knockdown in astrocytes was used to test causality.
RESULTS: Sleep deprivation significantly worsened motor deficits, dopaminergic neuron loss, and α-syn pathology in PD mice. It induced astrocyte reactivity and disrupted aquaporin-4 (AQP4) polarization, leading to impaired cerebrospinal fluid influx and reduced α-syn clearance. LAG3 was selectively upregulated in astrocytes under sleep-deprived conditions and promoted α-syn PFF internalization. Knockdown of astrocytic LAG3 restored AQP4 polarization, improved glymphatic clearance, and attenuated neurodegeneration and behavioral deficits.
CONCLUSION: Our findings identify astrocytic LAG3 as a critical mediator linking sleep deprivation to glymphatic dysfunction and PD progression. Targeting LAG3 may represent a promising, albeit early-stage, therapeutic strategy to mitigate α-syn pathology in PD patients with sleep disorders.