Upregulation of ELFN2 in TDP-43 Knockout Neurons Suggests a Compensatory Mechanism Modulating Glutamatergic Signaling on Chromosome 22

Transactive response DNA-binding protein 43 kDa (TDP-43) is a critical regulator of RNA metabolism in neurons, and its loss of function is central to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While global transcriptional consequences of TDP-43 depletion have been described, chromosome-specific downstream responses affecting synaptic regulation remain poorly defined. In this study, we performed a focused transcriptomic analysis of chromosome 22 in TDP-43 knockout (KO) neurons using RNA-sequencing data from the GSE136366 dataset. Differential expression analysis was conducted between three KO and three wild-type samples following quality control, transcript quantification, and normalization. Out of 534 expressed genes on chromosome 22, 11 genes were significantly differentially expressed (adjusted p-value < 0.05, |log2 fold-change| ≥ 1), including nine upregulated and two downregulated genes in TDP-43 KO neurons. Among these, ELFN2, a postsynaptic adhesion molecule that modulates group III metabotropic glutamate receptor (mGluR) signaling, showed robust upregulation (log2 fold-change = 1.70, adjusted p-value = 9.18 × 10⁻¹⁰). Sample clustering, correlation analysis, and principal component analysis demonstrated strong separation between KO and wild-type groups, indicating consistent biological effects of TDP-43 loss. Functional enrichment analysis highlighted signaling-related molecular functions, supporting a role for synaptic modulation. The upregulation of ELFN2 in TDP-43-deficient neurons suggests a potential compensatory mechanism aimed at restraining glutamatergic excitability through enhanced group III mGluR signaling. These findings identify ELFN2 as a candidate molecular marker of adaptive synaptic regulation following TDP-43 loss and provide insight into chromosome-specific transcriptional responses relevant to ALS-associated neurodegeneration