Regulation of the Innate Immune System as a Therapeutic Approach to Supporting Respiratory Function in ALS

McGrath, Michael S.; Zhang, Rongzhen; Bracci, Paige M.; Azhir, Ari; Forrest, Bruce D.

doi:10.3390/cells12071031

Cited by 7 publications

(1 citation statement)

References 43 publications

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“…This is further associated increased abundance of C3 and the receptor for its C3a cleavage product (C3AR1) near ALS motor neurons ( Woodruff et al, 2008 ; Heurich et al, 2011 ; Bahia El Idrissi et al, 2016 ), which can indirectly enhance neutrophil recruitment via their effect on other immune cells ( Daffern et al, 1995 ; Warwick et al, 2021 ). These results underscore a nexus of innate immune cells and immunomodulatory proteins in ALS, bolstering the rationale for development of drug candidates targeting innate immune pathways ( Miller R. G. et al, 2022 ; Zhang R. et al, 2022 ; McGrath et al, 2023 ).…”

Section: Discussionmentioning

confidence: 67%

Meta-analysis of differential gene expression in lower motor neurons isolated by laser capture microdissection from post-mortem ALS spinal cords

Swindell

2024

Front. Genet.

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IntroductionALS is a fatal neurodegenerative disease for which underlying mechanisms are incompletely understood. The motor neuron is a central player in ALS pathogenesis but different transcriptome signatures have been derived from bulk analysis of post-mortem tissue and iPSC-derived motor neurons (iPSC-MNs).MethodsThis study performed a meta-analysis of six gene expression studies (microarray and RNA-seq) in which laser capture microdissection (LCM) was used to isolate lower motor neurons from post-mortem spinal cords of ALS and control (CTL) subjects. Differentially expressed genes (DEGs) with consistent ALS versus CTL expression differences across studies were identified.ResultsThe analysis identified 222 ALS-increased DEGs (FDR <0.10, SMD >0.80) and 278 ALS-decreased DEGs (FDR <0.10, SMD < −0.80). ALS-increased DEGs were linked to PI3K-AKT signaling, innate immunity, inflammation, motor neuron differentiation and extracellular matrix. ALS-decreased DEGs were associated with the ubiquitin-proteosome system, microtubules, axon growth, RNA-binding proteins and synaptic membrane. ALS-decreased DEG mRNAs frequently interacted with RNA-binding proteins (e.g., FUS, HuR). The complete set of DEGs (increased and decreased) overlapped significantly with genes near ALS-associated SNP loci (p < 0.01). Transcription factor target motifs with increased proximity to ALS-increased DEGs were identified, most notably DNA elements predicted to interact with forkhead transcription factors (e.g., FOXP1) and motor neuron and pancreas homeobox 1 (MNX1). Some of these DNA elements overlie ALS-associated SNPs within known enhancers and are predicted to have genotype-dependent MNX1 interactions. DEGs were compared to those identified from SOD1-G93A mice and bulk spinal cord segments or iPSC-MNs from ALS patients. There was good correspondence with transcriptome changes from SOD1-G93A mice (r ≤ 0.408) but most DEGs were not differentially expressed in bulk spinal cords or iPSC-MNs and transcriptome-wide effect size correlations were weak (bulk tissue: r ≤ 0.207, iPSC-MN: r ≤ 0.037).ConclusionThis study defines a robust transcriptome signature from LCM-based motor neuron studies of post-mortem tissue from ALS and CTL subjects. This signature differs from those obtained from analysis of bulk spinal cord segments and iPSC-MNs. Results provide insight into mechanisms underlying gene dysregulation in ALS and highlight connections between these mechanisms, ALS genetics, and motor neuron biology.

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Section: Discussionmentioning

confidence: 67%

Meta-analysis of differential gene expression in lower motor neurons isolated by laser capture microdissection from post-mortem ALS spinal cords

Swindell

2024

Front. Genet.

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Retina Oculomics in Neurodegenerative Disease

Suh,

Ong,

Kamran

et al. 2023

Ann Biomed Eng

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The role of macrophage plasticity in neurodegenerative diseases

Ma,

Zhu,

Chen

et al. 2024

Biomark Res

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Tissue-resident macrophages and recruited macrophages play pivotal roles in innate immunity and the maintenance of brain homeostasis. Investigating the involvement of these macrophage populations in eliciting pathological changes associated with neurodegenerative diseases has been a focal point of research. Dysregulated states of macrophages can compromise clearance mechanisms for pathological proteins such as amyloid-β (Aβ) in Alzheimer’s disease (AD) and TDP-43 in Amyotrophic lateral sclerosis (ALS). Additionally, recent evidence suggests that abnormalities in the peripheral clearance of pathological proteins are implicated in the pathogenesis and progression of neurodegenerative diseases. Furthermore, numerous genome-wide association studies have linked genetic risk factors, which alter the functionality of various immune cells, to the accumulation of pathological proteins. This review aims to unravel the intricacies of macrophage biology in both homeostatic conditions and neurodegenerative disorders. To this end, we initially provide an overview of the modifications in receptor and gene expression observed in diverse macrophage subsets throughout development. Subsequently, we outlined the roles of resident macrophages and recruited macrophages in neurodegenerative diseases and the progress of targeted therapy. Finally, we describe the latest advances in macrophage imaging methods and measurement of inflammation, which may provide information and related treatment strategies that hold promise for informing the design of future investigations and therapeutic interventions.

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Regulation of the Innate Immune System as a Therapeutic Approach to Supporting Respiratory Function in ALS

Cited by 7 publications

References 43 publications

Meta-analysis of differential gene expression in lower motor neurons isolated by laser capture microdissection from post-mortem ALS spinal cords

Meta-analysis of differential gene expression in lower motor neurons isolated by laser capture microdissection from post-mortem ALS spinal cords

Retina Oculomics in Neurodegenerative Disease

The role of macrophage plasticity in neurodegenerative diseases

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