Sleep deprivation accelerates Parkinson's disease pathology by upregulating LAG3 in astrocytes and disrupting...

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.

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.

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.

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.

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.