Bone Marrow Stromal Cell Antigen 2: Is a Potential Neuroinflammation Biomarker of SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis in Pre-symptomatic Stage.

Xiaojiao Xu,Jingjing Zhang,Murad Al-Nusaif,Song Li,Qinming Zhou,Weidong Le,Sheng Chen

doi:10.3389/fnins.2021.788730

Abstract

Neuroinflammation has long been thought to be associated with amyotrophic lateral sclerosis (ALS) development and progression. However, the exact molecular mechanisms of neuroinflammation underlying ALS remain largely unknown. In the present study, we attempted to elucidate the genetic basis of neuroinflammation in ALS by comparing the transcriptomic profile of the anterior horns of the lumbar spinal cord (AHLSC) between SOD1G93A mice and their wild-type (WT) littermates. Our results revealed that immune-related genes were selectively up-regulated in the AHLSC of pre-symptomatic ALS mice (40 days of age) compared to age-matched WT control mice. Notably, the differential expression level of these immune-related genes became more significant at the symptomatic stage of disease (90 days of age) in the ALS mice. Subsequently, eight genes involved in innate immune response in the AHLSC of ALS mice were further validated by qRT-PCR analysis. Of these genes, bone marrow stromal cell antigen 2 (BST2) was found for the first time to be significantly higher in the AHLSC of pre-symptomatic ALS mice when compared with WT mice. The increasing trend of BST2 expression became more obvious in the symptomatic stage. Immunofluorescent staining further confirmed that BST2 is mainly expressed on microglia in the AHLSC of ALS mice. These findings support the view that immune-related neuroinflammation is involved in the early pathogenesis of ALS, and BST2 may serve as a potential target for ameliorating microglia-mediated neuroinflammation pathologies in ALS.

Highlights

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons (MNs) (Brown and Al-Chalabi, 2017)
EdgeR in the setting of a GLM was used to identify differential expression genes (DEGs). 254 and 524 genes were found differentially expressed between SOD1G93A mice and WT mice in the anterior horns of the lumbar spinal cord (AHLSC) of 40 and 90 days, respectively (Figure 1B)
Considering that inflammation is a central characteristic of an effective immune response (Brady et al, 2018; McCauley and Baloh, 2019), these results might indicate that SOD1G93A can selectively influence the neuroinflammation gene expressions of ALS mice in the early stage

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons (MNs) (Brown and Al-Chalabi, 2017). The average age of disease onset of ALS is 40–70 years, and the clinical manifestations may include limb weakness, muscle atrophy, dysphagia, dysarthria, etc. The majority (more than 90%) of ALS cases are sporadic, whereas a minor fraction (about 5– 10%) is familial. Mutations in Cu/Zn superoxide dismutase 1 (SOD1), the first identified gene in ALS, characterize more than 20% of familial and 1–4% of sporadic ALS cases (Liu et al, 2018). Due to the obscure etiology and complex mechanism of ALS, effective prevention measures and treatments are still absent in clinical practice. In this way, the exploration of early diagnostic biomarkers and specific therapeutic targets are urgently needed

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Results

Conclusion