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Exploring Common Therapeutic Targets for Neurodegenerative Disorders Using Transcriptome Study
S Akila Parvathy Dharshini1, Sherlyn Jemimah1, Y H Taguchi2
1Protein Bioinformatics Lab, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, India.
Abstract:
Alzheimer's disease (AD) and Parkinson's disease (PD) are well-known neuronal degenerative disorders that share common pathological events. Approved medications alleviate symptoms but do not address the root cause of the disease. Energy dysfunction in the neuronal population leads to various pathological events and ultimately results in neuronal death. Identifying common therapeutic targets for these disorders may help in the drug discovery process. The Brodmann area 9 (BA9) region is affected in both the disease conditions and plays an essential role in cognitive, motor, and memory-related functions. Analyzing transcriptome data of BA9 provides deep insights related to common pathological pathways involved in AD and PD. In this work, we map the preprocessed BA9 fastq files generated by RNA-seq for disease and control samples with reference hg38 genomic assembly and identify common variants and differentially expressed genes (DEG). These variants are predominantly located in the 3' UTR (non-promoter) region, affecting the conserved transcription factor (TF) binding motifs involved in the methylation and acetylation process. We have constructed BA9-specific functional interaction networks, which show the relationship between TFs and DEGs. Based on expression signature analysis, we propose that MAPK1, VEGFR1/FLT1, and FGFR1 are promising drug targets to restore blood-brain barrier functionality by reducing neuroinflammation and may save neurons.
Insights
Researchers identified common genetic variants and gene expression changes in Brodmann area 9 (BA9) for Alzheimer's disease (AD) and Parkinson's disease (PD). They propose MAPK1, VEGFR1/FLT1, and FGFR1 as potential drug targets to reduce neuroinflammation and protect neurons.
Area of Science:
- Neuroscience
- Genomics
- Pharmacology
Background:
- Alzheimer's disease (AD) and Parkinson's disease (PD) are neurodegenerative disorders with shared pathological pathways, but current treatments only manage symptoms.
- Neuronal energy dysfunction contributes to pathogenesis and eventual cell death in these conditions.
- The Brodmann area 9 (BA9) is implicated in both AD and PD, affecting cognitive, motor, and memory functions.
Purpose of the Study:
- To identify common therapeutic targets for AD and PD by analyzing transcriptome data from the BA9 region.
- To investigate shared pathological pathways and genetic variations in BA9 relevant to both neurodegenerative diseases.
Main Methods:
- RNA-sequencing (RNA-seq) was used to analyze BA9 transcriptome data from disease and control samples.
- Fastq files were mapped to the hg38 human genome assembly to identify common variants and differentially expressed genes (DEGs).
- Functional interaction networks were constructed to analyze relationships between transcription factors (TFs) and DEGs.
Main Results:
- Common genetic variants were identified, primarily in the 3' UTR region, impacting TF binding motifs involved in epigenetic regulation (methylation and acetylation).
- Differentially expressed genes (DEGs) were identified in BA9, suggesting shared molecular pathways in AD and PD.
- Functional networks revealed interactions between TFs and DEGs, highlighting key regulatory mechanisms.
Conclusions:
- MAPK1, VEGFR1/FLT1, and FGFR1 are proposed as promising therapeutic targets based on expression signature analysis.
- Targeting these genes may restore blood-brain barrier function, reduce neuroinflammation, and protect neurons in AD and PD.
- This study provides insights into common pathogenic mechanisms and potential drug targets for neurodegenerative diseases.
