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Comparative Study
. 2024 May 16;19(5):e0301267.
doi: 10.1371/journal.pone.0301267. eCollection 2024.

Understanding the relationship between cerebellum and the frontal-cortex region of C9orf72-related amyotrophic lateral sclerosis: A comparative analysis of genetic features

Kartikay Prasad  1 , Md Imtaiyaz Hassan  2 , Saurabh Raghuvanshi  3 , Vijay Kumar  1
Affiliations
Comparative Study

Understanding the relationship between cerebellum and the frontal-cortex region of C9orf72-related amyotrophic lateral sclerosis: A comparative analysis of genetic features

Kartikay Prasad et al. PLoS One. .

Abstract

Background: Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal neurodegenerative diseases for which at present no cure is available. Despite the extensive research the progress from diagnosis to prognosis in ALS and frontotemporal dementia (FTD) has been slow which represents suboptimal understanding of disease pathophysiological processes. In recent studies, several genes have been associated with the ALS and FTD diseases such as SOD1, TDP43, and TBK1, whereas the hexanucleotide GGGGCC repeat expansion (HRE) in C9orf72 gene is a most frequent cause of ALS and FTD, that has changed the understanding of these diseases.

Methods: The goal of this study was to identify and spatially determine differential gene expression signature differences between cerebellum and frontal cortex in C9orf72-associated ALS (C9-ALS), to study the network properties of these differentially expressed genes, and to identify miRNAs targeting the common differentially expressed genes in both the tissues. This study thus highlights underlying differential cell susceptibilities to the disease mechanisms in C9-ALS and suggesting therapeutic target selection in C9-ALS.

Results: In this manuscript, we have identified that the genes involved in neuron development, protein localization and transcription are mostly enriched in cerebellum of C9-ALS patients, while the UPR-related genes are enriched in the frontal cortex. Of note, UPR pathway genes were mostly dysregulated both in the C9-ALS cerebellum and frontal cortex. Overall, the data presented here show that defects in normal RNA processing and the UPR pathway are the pathological hallmarks of C9-ALS. Interestingly, the cerebellum showed more strong transcriptome changes than the frontal cortex.

Conclusion: Interestingly, the cerebellum region showed more significant transcriptomic changes as compared to the frontal cortex region suggesting its active participation in the disease process. This nuanced understanding may offer valuable insights for the development of targeted therapeutic strategies aimed at mitigating disease progression in C9-ALS.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Differential gene expression analysis of cerebellum tissue samples.
(A) Heatmap of the differentially expressed genes (Pval < 0.01 & FDR < 0.01) in Cerebellum region of the C9ALS patients. (B) Bar plot representing DEGs count.
Fig 2
Fig 2. Differential gene expression analysis of Frontal-cortex tissue samples.
(A) Heatmap of the differentially expressed genes (Pval < 0.01 & FDR < 0.01) in Frontal cortex region of the C9ALS patients. (B) Bar plot representing DEGs count.
Fig 3
Fig 3. Gene Ontology and pathway enrichment analysis.
(A) Gene-Set Enrichment Analysis of the dysregulated protein coding genes in the Cerebellum region. (B) Pathways Enrichment Analysis of the dysregulated protein coding genes using KEGG Pathways.
Fig 4
Fig 4. Gene Ontology and pathway enrichment analysis.
(A) Gene-Set Enrichment Analysis of the dysregulated protein coding genes in the Frontal Cortex region. (B) Pathways Enrichment Analysis of the dysregulated protein coding genes using KEGG Pathways.
Fig 5
Fig 5
(A) Venn based analysis to identify common upregulated genes in cerebellum and frontal cortex region. (B) Venn based analysis to identify common downregulated genes in cerebellum and frontal cortex region.
Fig 6
Fig 6
(A) Interaction network of common upregulated genes (in red) with the genes elevated in the brain region (in blue). (B) Downregulated OPN1SW gene interacts with only one gene GNG13.
Fig 7
Fig 7
(A) Disease-gene interaction network of common upregulated genes along with the interacting genes enriched in brain region. (B) Disease-gene interaction network of common downregulated genes along with the interacting genes enriched in brain region.
Fig 8
Fig 8
(A) miRNA-gene interaction network of common upregulated genes. (B) miRNA-gene interaction network of common downregulated gene (miRNAs are highlighted in pink color nodes).
Fig 9
Fig 9
(A) Gene-Ontology analysis of miRNAs interacting with the upregulated genes. (B) Pathways enrichment analysis of the interacting miRNAs.
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Grants and funding

K.P. sincerely thanks the Indian Council of Medical Research (ICMR) New Delhi, India for providing the Senior Research Fellowship grant (BMI/11(63)/2020). VK sincerely thanks Indian Council of Medical Research (ICMR) New Delhi, India (Grant No. DHR/Neuro/2020-NCD-I). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.