ABSTRACT
Suppressor of Mek1 (Smek1) is a regulatory subunit of protein phosphatase 4. Genome-wide association studies have shown the protective effect of SMEK1 in Alzheimer's disease (AD). However, the physiological and pathological roles of Smek1 in AD and other tauopathies are largely unclear. Here, the role of Smek1 in preventing neurodegeneration is investigated in tauopathy. Smek1 is downregulated in the aged human brain. Through single-cell sequencing, a novel neuronal cluster is identified that possesses neurodegenerative characteristics in Smek1-/- mice. Smek1 deficiency caused markedly more severe motor and cognitive impairments in mice, as well as neuronal loss, gliosis, and tau hyperphosphorylation at major glycogen synthase kinase 3ß (Gsk3ß) sites. Protein-protein interaction analysis revealed that the Ran-binding domain (RanBD) in the N-terminus of Smek1 facilitated binding with kinesin family member 2A (Kif2a). Depletion of Smek1 resulted in cytoplasmic aggregation of Kif2a, axon outgrowth defects, and impaired mitochondrial axonal trafficking. Downregulation of Kif2a markedly attenuated tau hyperphosphorylation and axon outgrowth defects in shSmek1 cells. For the first time, this study demonstrates that Smek1 deficiency progressively induces neurodegeneration by exacerbating tau pathology and mitochondrial dysfunction in an age-dependent manner.
ABSTRACT
PURPOSE: Anti-gamma-aminobutyric acid B receptor (GABABR) encephalitis is an uncommon form of autoimmune encephalitis associated with a poor prognosis and a high fatality rate. We aim to find diagnostic markers for anti- GABABR encephalitis as well as the effects of immune cell infiltration on this pathology. METHODS: For quantitative proteomic analysis, isobaric tags for relative and absolute quantitation were used in conjunction with LC-MS/MS analysis. To conduct functional correlation analyses, differentially expressed proteins (DEPs) were identified. Following that, we used bioinformatics analysis to screen for and determine the diagnostic signatures of anti- GABABR encephalitis. ROC curves were used to evaluate the diagnostic values. To assess the inflammatory status of anti- GABABR encephalitis, we used cell-type identification by estimating relative subsets of the RNA transcript (CIBERSORT) and explored the link between diagnostic markers and infiltrating immune cells. RESULTS: Overall, 108 robust DEPs (47 upregulated and 61 downregulated) were identified, of which 11 were immune related. The most impressively enriched pathways were complemented and coagulation cascades, actin cytoskeleton regulation, and cholesterol metabolism; GSEA revealed that the enriched pathways were considerably differentially connected to immune modulation. Eleven immune-related DEPs were chosen for further investigation. We developed a novel diagnostic model based on CSF1R and AZGP1 serum levels using ROC analysis (area under the ROC curve = 1). M1 macrophages and activated natural killer cells are likely to play a role in course of anti- GABABR encephalitis. CONCLUSION: We identified CSF1R and AZGP1 are possible anti-GABABR encephalitis diagnostic indicators, and immune cell infiltration may have a significant impact on the development and occurrence of anti- GABABR encephalitis.