Single-cell RNA sequencing of CSF reveals neuroprotective RAC1 NK cells in Parkinson's disease.

Brain infiltration of the natural killer (NK) cells has been observed in several neurodegenerative disorders, including Parkinson's disease (PD). In a mouse model of α-synucleinopathy, it has been shown that NK cells help in clearing α-synuclein (α-syn) aggregates. This study aimed to investigate the molecular mechanisms underlying the brain infiltration of NK cells in PD. Immunofluorescence assay was performed using the anti-NKp46 antibody to detect NK cells in the brain of PD model mice. Next, we analyzed the publicly available single-cell RNA sequencing (scRNA-seq) data (GSE141578) of the cerebrospinal fluid (CSF) from patients with PD to characterize the CSF immune landscape in PD. Results showed that NK cells infiltrate the substantia nigra (SN) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model mice and colocalize with dopaminergic neurons and α-syn. Moreover, the ratio of NK cells was found to be increased in the CSF of PD patients. Analysis of the scRNA-seq data revealed that Rac family small GTPase 1 (RAC1) was the most significantly upregulated gene in NK cells from PD patients. Furthermore, genes involved in regulating SN development were enriched in RAC1 NK cells and these cells showed increased brain infiltration in MPTP-induced PD mice. In conclusion, NK cells actively home to the SN of PD model mice and RAC1 might be involved in regulating this process. Moreover, RAC1 NK cells play a neuroprotective role in PD.