Neurodegenerative diseases represent a growing global health burden as populations age. The authors sought to identify common molecular mechanisms across Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD) by comparing patient transcriptomic profiles, with the specific aim of nominating candidate gene targets suitable for drug repurposing.
Their rationale is that shared dysregulated pathways and genes could reveal convergent disease biology and point to existing, approved drugs with potential therapeutic value across multiple neurodegenerative diagnoses.
The study analyzed transcriptomic profiles from patient datasets for each disease to detect differentially expressed genes (DEGs) and to perform pathway enrichment analysis. The authors then identified genes common to the enriched pathways across all three diseases and carried out in silico validation to evaluate the impact of dysregulation on these candidate targets.
Footnotes in the article reference multiple GEO accessions used as data sources and provide a GitHub repository for code and supplementary material, indicating an intent toward reproducibility. The GEO accession identifiers and the GitHub link are reported in the article footnotes.
Comparative analysis across the disease-specific transcriptomes identified 274 common differentially expressed genes. These genes were shared across AD, PD, and HD and served as the basis for subsequent pathway enrichment and target nomination.
The article reports that these common DEGs participate in pathways that were consistently upregulated across the three neurodegenerative conditions, supporting a degree of shared molecular perturbation despite distinct clinical phenotypes.
Three pathways were found to be enriched and upregulated across all three diseases. Two of these pathways converge on activation of the transcription factor NF-κB, highlighting a shared inflammatory or immune signaling axis in AD, PD, and HD. The third pathway involves regulation of BCL2L11 transcription by RUNX3; this axis is discussed in the context of mechanisms that may underlie the epidemiological observation that neurodegenerative disease cohorts sometimes show reduced cancer incidence.
Together, these findings suggest overlapping processes of inflammation and apoptosis/regulation of cell survival that may be common contributors to neurodegeneration across diagnostic categories.
From the set of shared pathways and DEGs, five genes were highlighted as key candidate drug targets because they were significantly upregulated in all three diseases and are involved in the shared pathways:
Three of these (NFKB1, RELA, and NFKBIA) are central components or regulators of the NF-κB transcriptional complex, supporting the interpretation that NF-κB–driven inflammatory signaling is a convergent feature. TRIM4 and SMAD4 were also implicated via their involvement in the enriched pathways; the specific mechanistic roles in each disease context are reported at the gene/pathway level.
The authors compiled a list of drugs previously approved by the US Food and Drug Administration that target the expression of the nominated genes. Rather than enumerating single agents in the abstract and front matter, the report highlights broad drug classes identified as potential repurposing candidates. These include commonly used and generally well tolerated medications such as antihyperlipidemics, antihypertensives, antidiabetics, analgesics, diuretics, antiparkinsonian agents, and antipsychotics.
The implication is that modulation of the expression or activity of the five nominated genes might be achievable using existing drugs from these therapeutic classes, enabling a repurposing strategy that could accelerate translational testing.
The study reports in silico validation of nominated targets to evaluate the impact of their dysregulation. The article footnotes list GEO accession numbers for the transcriptomic datasets used and provide a GitHub repository containing code and supplementary files, which supports reproducibility and further exploration by other investigators.
However, the high-level summary provided in the article front matter does not detail the specific computational pipelines, exact statistical thresholds used for DEG calling, or the metrics applied in the in silico validation; those methodological specifics appear in the full text or supplementary materials linked in the article but were not included in the abstract-level material presented here.
The analysis highlights shared inflammatory signaling through NF-κB and a RUNX3–BCL2L11 regulatory axis as common features across AD, PD, and HD, and nominates five upregulated genes (NFKBIA, NFKB1, RELA, TRIM4, SMAD4) as candidate drug targets. By mapping these targets to FDA‑approved drug classes, the study proposes avenues for drug repurposing across neurodegenerative diseases.
This work is presented as a preprint and has not undergone peer review. The abstract and front matter summarize major results and resources but do not provide complete methodological detail in the excerpt available here; readers should consult the full manuscript and supplementary material for full methods, statistical criteria, and validation results before drawing clinical conclusions. The effectiveness and safety of any repurposed drug interventions would require rigorous preclinical and clinical evaluation despite the existing approval status of the drugs identified.
Data and code availability are indicated via GEO accession numbers and a GitHub repository listed in the article footnotes, facilitating independent verification and follow-up studies.
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