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Role of NCKAP1 in the Defective Phagocytic Function of Microglia-Like Cells Derived from Rapidly Progressing Sporadic ALS

Authors
Noh, Min-YoungKwon, Min-SooOh, Ki-WookNahm, MinyeopPark, JinseokKim, Young-EunKi, Chang-SeokJin, Hee KyungBae, Jae-sungKim, Seung Hyun
Issue Date
Aug-2023
Publisher
Humana Press, Inc.
Keywords
Amyotrophic Lateral Sclerosis; Microglia; NCKAP1; Phagocytosis
Citation
Molecular Neurobiology, v.60, no.8, pp.4761 - 4777
Journal Title
Molecular Neurobiology
Volume
60
Number
8
Start Page
4761
End Page
4777
URI
http://scholarworks.bwise.kr/kbri/handle/2023.sw.kbri/132
DOI
10.1007/s12035-023-03339-2
ISSN
0893-7648
Abstract
Microglia plays a key role in determining the progression of amyotrophic lateral sclerosis (ALS), yet their precise role in ALS has not been identified in humans. This study aimed to identify a key factor related to the functional characteristics of microglia in rapidly progressing sporadic ALS patients using the induced microglia model, although it is not identical to brain resident microglia. After confirming that microglia-like cells (iMGs) induced by human monocytes could recapitulate the main signatures of brain microglia, step-by-step comparative studies were conducted to delineate functional differences using iMGs from patients with slowly progressive ALS [ALS(S), n = 14] versus rapidly progressive ALS [ALS(R), n = 15]. 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. Post-hoc analysis indicated that decreased NCKAP1 expression in iMGs was correlated with the progression of ALS. Our data suggest that microglial NCKAP1 may be an alternative therapeutic target in rapidly progressive sporadic ALS.
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