Defective phagocytic function of induced microglia-like cells is correlated with rapid progression of sporadic ALS

Abstract

Background: Microglia play a key role in determining the progression of amyotrophic lateral sclerosis (ALS), yet their precise role in ALS has not been identified in humans. The objective of this study was to identify the functional characteristics of microglia and related factors in patients with sporadic ALS that is rapidly progressing.Methods: After confirming that microglia-like cells (iMGs) induced by human monocytes could recapitulate the main signatures of brain microglia, serial comparative studies were conducted to delineate functional differences in iMGs from patients with slowly progressive ALS [ALS(S), n = 14] versus rapidly progressive ALS [ALS(R), n = 15].Results: Despite an absence of significant differences in the expression of microglial homeostatic genes, ALS(R)-iMGs preferentially showed defective phagocytosis and an exaggerated pro-inflammatory response to LPS stimuli compared to ALS(S)-iMGs. Transcriptome analysis revealed that the perturbed phagocytosis seen in ALS(R)-iMGs was closely associated with decreased NCKAP1 (NCK-associated protein 1)-mediated abnormal actin polymerization. NCKAP1 overexpression was sufficient to rescue impaired phagocytosis in ALS(R)-iMGs. To leverage our findings and identify biological markers of rapidly progressing ALS, we measured plasma miRNA-214-3p (negative regulator targeting NCKAP1) levels. Post-hoc analysis indicated that decreased NCKAP1 expression in iMGs and a concomitant increase in plasma miRNA-214-3p levels was correlated with rapid progression of ALS.Interpretation: Our data suggest that microglial NCKAP1 may be an alternative therapeutic target in rapidly progressive sporadic ALS. In addition, miRNA-214-3p levels could be a serological biomarker for predicting the speed of disease progression.

Regulation of the HTRA2 Protease Activity by an Inhibitory Antibody-Derived Peptide Ligand and the Influence on HTRA2-Specific Protein Interaction Networks in Retinal Tissues

“…Disturbed APP processing can result in neurotoxic amyloid plaque formation, which is one of the main hallmarks in AD [ 49 ] and was also observed in a chronic glaucoma animal model [ 50 ]. In addition, in the microglia of amyotrophic lateral sclerosis (ALS) patients, the decreased expression of NCKAP1 was also significantly correlated with defective phagocytic function and abnormal actin polymerization [ 51 ]. However, it can be assumed that both proteins AP3D1 and NCKAP1 are potential substrate molecules of HTRA2 binding to the catalytic domain, as enrichment was clearly inhibited in the UCF-101 or the CDR group (see Figure 3 A and Figure S3 ).…”