TY - JOUR

T1 - Integrative genetic and single cell RNA sequencing analysis provides new clues to the amyotrophic lateral sclerosis neurodegeneration

AU - Liu, Hankui

AU - Guan, Liping

AU - Deng, Min

AU - Bolund, Lars

AU - Kristiansen, Karsten

AU - Zhang, Jianguo

AU - Luo, Yonglun

AU - Zhang, Zhanchi

N1 - Publisher Copyright: Copyright © 2023 Liu, Guan, Deng, Bolund, Kristiansen, Zhang, Luo and Zhang.

PY - 2023

Y1 - 2023

N2 - Introduction: The gradual loss of motor neurons (MNs) in the brain and spinal cord is a hallmark of amyotrophic lateral sclerosis (ALS), but the mechanisms underlying neurodegeneration in ALS are still not fully understood. Methods: Based on 75 ALS-pathogenicity/susceptibility genes and large-scale single-cell transcriptomes of human/mouse brain/spinal cord/muscle tissues, we performed an expression enrichment analysis to identify cells involved in ALS pathogenesis. Subsequently, we created a strictness measure to estimate the dosage requirement of ALS-related genes in linked cell types. Results: Remarkably, expression enrichment analysis showed that α- and γ-MNs, respectively, are associated with ALS-susceptibility genes and ALS-pathogenicity genes, revealing differences in biological processes between sporadic and familial ALS. In MNs, ALS-susceptibility genes exhibited high strictness, as well as the ALS-pathogenicity genes with known loss of function mechanism, indicating the main characteristic of ALS-susceptibility genes is dosage-sensitive and the loss of function mechanism of these genes may involve in sporadic ALS. In contrast, ALS-pathogenicity genes with gain of function mechanism exhibited low strictness. The significant difference of strictness between loss of function genes and gain of function genes provided a priori understanding for the pathogenesis of novel genes without an animal model. Besides MNs, we observed no statistical evidence for an association between muscle cells and ALS-related genes. This result may provide insight into the etiology that ALS is not within the domain of neuromuscular diseases. Moreover, we showed several cell types linked to other neurological diseases [i.e., spinocerebellar ataxia (SA), hereditary motor neuropathies (HMN)] and neuromuscular diseases [i.e. hereditary spastic paraplegia (SPG), spinal muscular atrophy (SMA)], including an association between Purkinje cells in brain and SA, an association between α-MNs in spinal cord and SA, an association between smooth muscle cells and SA, an association between oligodendrocyte and HMN, a suggestive association between γ-MNs and HMN, a suggestive association between mature skeletal muscle and HMN, an association between oligodendrocyte in brain and SPG, and no statistical evidence for an association between cell type and SMA. Discussion: These cellular similarities and differences deepened our understanding of the heterogeneous cellular basis of ALS, SA, HMN, SPG, and SMA.

AB - Introduction: The gradual loss of motor neurons (MNs) in the brain and spinal cord is a hallmark of amyotrophic lateral sclerosis (ALS), but the mechanisms underlying neurodegeneration in ALS are still not fully understood. Methods: Based on 75 ALS-pathogenicity/susceptibility genes and large-scale single-cell transcriptomes of human/mouse brain/spinal cord/muscle tissues, we performed an expression enrichment analysis to identify cells involved in ALS pathogenesis. Subsequently, we created a strictness measure to estimate the dosage requirement of ALS-related genes in linked cell types. Results: Remarkably, expression enrichment analysis showed that α- and γ-MNs, respectively, are associated with ALS-susceptibility genes and ALS-pathogenicity genes, revealing differences in biological processes between sporadic and familial ALS. In MNs, ALS-susceptibility genes exhibited high strictness, as well as the ALS-pathogenicity genes with known loss of function mechanism, indicating the main characteristic of ALS-susceptibility genes is dosage-sensitive and the loss of function mechanism of these genes may involve in sporadic ALS. In contrast, ALS-pathogenicity genes with gain of function mechanism exhibited low strictness. The significant difference of strictness between loss of function genes and gain of function genes provided a priori understanding for the pathogenesis of novel genes without an animal model. Besides MNs, we observed no statistical evidence for an association between muscle cells and ALS-related genes. This result may provide insight into the etiology that ALS is not within the domain of neuromuscular diseases. Moreover, we showed several cell types linked to other neurological diseases [i.e., spinocerebellar ataxia (SA), hereditary motor neuropathies (HMN)] and neuromuscular diseases [i.e. hereditary spastic paraplegia (SPG), spinal muscular atrophy (SMA)], including an association between Purkinje cells in brain and SA, an association between α-MNs in spinal cord and SA, an association between smooth muscle cells and SA, an association between oligodendrocyte and HMN, a suggestive association between γ-MNs and HMN, a suggestive association between mature skeletal muscle and HMN, an association between oligodendrocyte in brain and SPG, and no statistical evidence for an association between cell type and SMA. Discussion: These cellular similarities and differences deepened our understanding of the heterogeneous cellular basis of ALS, SA, HMN, SPG, and SMA.

KW - amyotrophic lateral sclerosis (ALS)

KW - genome-wide association studies (GWAS)

KW - motor neurons (MNs)

KW - neurological disorder

KW - single-cell transcriptome

U2 - 10.3389/fnins.2023.1116087

DO - 10.3389/fnins.2023.1116087

M3 - Journal article

C2 - 36875658

AN - SCOPUS:85149700113

VL - 17

JO - Frontiers in Neuroscience

JF - Frontiers in Neuroscience

SN - 1662-4548

M1 - 1116087

ER -