Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Early loss of bone mass in the SOD1(G93A) ALS mouse model is associated with loss of sensitivity to osteogenic factors and enhanced bone senescence

ABSTRACT: Amyotrophic lateral sclerosis (ALS) is conceptualized as a progressive motor neuron degeneration, but emerging evidence suggests systemic manifestations beyond the neuromuscular system. Altered bone structure and metabolism has been shown to be part of the ALS clinical presentation; it remains unclear whether the bone phenotype is secondary to muscle denervation and reduced loading, or it is due to an autonomous process. We investigated skeletal involvement in the SOD1(G93A) mouse model at presymptomatic (P45) and symptomatic (P110) stage through biomechanical and transcriptomic approaches. Biomechanical three-point bending tests revealed significant reductions in femoral rigidity and maximum bending force in SOD1 mutants at P45, indicating early structural deficits. Micro-CT analysis demonstrated reduced trabecular bone mineral density and thickness at P45, with progressive trabecular loss and cortical thinning by P110. Histological examination revealed marked osteoblast loss at P45 with minimal changes in osteoclast activity, suggesting impaired bone formation as the primary early mechanism. Transcriptomic analysis of bone tissue and cultured osteoblasts from P45 mice identified dysregulation of bone differentiation pathways, including downregulation of osteoblast differentiation genes and upregulation of negative regulators of ossification. Notably, unfolded protein response was upregulated in SOD1 osteoblasts and E2F targets and G2M checkpoint genes were significantly downregulated. Immunohistochemistry confirmed increased p16Ink4a level in SOD1 osteoblasts, indicating cellular senescence as a key pathological mechanism. These findings suggest that bone deterioration in ALS reflects intrinsic defects in bone that precede motor symptoms. Understanding these mechanisms may lead to targeted interventions to preserve skeletal integrity in ALS patients and potentially reveal novel insights into ALS pathogenesis beyond the neuromuscular system.

INSTRUMENT(S): Illumina NovaSeq 6000

ORGANISM(S): Mus musculus

SUBMITTER: Burak Özkan

PROVIDER: E-MTAB-15734 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:We established iPSCs from healthy donors, SOD1-ALS and TDP43-ALS patients. Using our differentiation protocol originally developed by Reinhardt et al.,2013, we diferentiated these iPSCs toward spinal motor neurons (MNs) and reproduce ALS pathology in a dish. To extend our understanding of finding different molecular mechanisms and pathways related to SOD1- and TDP43 mutations in ALS disease, we have performed a comprehensive gene expression profiling study using RNA-Seq of the iPSC-derived MN models from control individuals and carefully compared with those from SOD1-ALS and TDP43-ALS patients. To generate novel hypotheses of putative underlying molecular mechanisms in ALS, we used human induced pluripotent stem cell (hiPSCs)-derived motor neurons (MNs) from SOD1- and TARDBP (TDP-43 protein)-mutant-ALS patients and healthy controls to perform high-throughput RNA-sequencing (RNA-Seq). An integrated bioinformatics approach was employed to identify differentially expressed genes (DEGs) and key pathways underlying these familial forms of the disease (fALS). In TDP43-ALS, we found dysregulation of transcripts encoding components of the transcriptional machinery and transcripts involved in splicing regulation were particularly affected. In contrast, less is known about the role of SOD1 in RNA metabolism in motor neurons. Here we found that many transcripts relevant for mitochondrial function were specifically altered in SOD1-ALS, indicating transcriptional signatures and expression patterns can vary significantly depending on the causal gene that is mutated. Surprisingly, however, we identified a clear downregulation of genes involved in protein translation in SOD1-ALS suggesting that ALS-causing SOD1 mutations shift cellular RNA abundance profiles to cause neural dysfunction. Altogether, we provided here an extensive profiling of mRNA expression in two ALS models at the cellular level, corroborating the major role of RNA metabolism and protein translation as a common pathomechanism in ALS

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Early loss of bone mass in the SOD1(G93A) ALS mouse model is associated with loss of sensitivity to osteogenic factors and enhanced bone senescence

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