Long genes are more frequently affected by somatic mutations and show reduced expression in Alzheimer's disease: Implications for disease etiology

Abstract

Aging, the greatest risk factor for Alzheimer's disease (AD), may lead to the accumulation of somatic mutations in neurons. We investigated whether somatic mutations, specifically in longer genes, are implicated in AD etiology. First, we modeled the theoretical likelihood of genes being affected by aging‐induced somatic mutations, dependent on their length. We then tested this model and found that long genes are indeed more affected by somatic mutations and that their expression is more frequently reduced in AD brains. Furthermore, using gene‐set enrichment analysis, we investigated the potential consequences of such long gene disruption. We found that long genes are involved in synaptic adhesion and other synaptic pathways that are predicted to be inhibited in the brains of AD patients. Taken together, our findings indicate that long gene–dependent synaptic impairment may contribute to AD pathogenesis.

Genome-wide RNA polymerase stalling shapes the transcriptome during aging

“…We show that approximately 40% of all elongating RNAPII complexes are stalled by DNA damage in WT aged livers; thus, the identical aging signal that causes progeroid syndromes also occurs in normal aging. Interestingly, brains from patients with Alzheimer’s disease also displayed reduced expression of long genes compared to age-matched controls 60 , suggesting that the magnitude of transcriptional stress is involved in age-related disease etiology. Conversely, longevity-promoting intervention dietary restriction restores the loss of long gene expression 29 , indicating that longevity interventions can alleviate transcriptional stress.…”

Purkinje-cell-specific DNA repair-deficient mice reveal that dietary restriction protects neurons by cell-intrinsic preservation of genomic health

“…Hence, analysis of gene-length-dependent transcriptional changes reflect a promising indirect readout for measuring transcription stress and the effect of DR in Ercc1 Δ/− nervous system. Importantly, a bias of reduced expression of long genes also has been found in aged human nervous system ( Vermeij et al, 2016a ; Niedernhofer et al, 2018 ; Soheili-Nezhad et al, 2021 ), indicating that DNA-damage-induced transcription stress is an important factor contributing to nervous system aging and targeted by DR ( Vermeij et al, 2016a ). Future studies employing high resolution spatial transcriptomic approaches ( Asp et al, 2020 ; Lewis et al, 2021 ) may uncover the relationships between transcriptional abnormalities and neuronal degeneration in aging and progeroid models.…”

RNA-binding protein ELAVL4/HuD ameliorates Alzheimer's disease-related molecular changes in human iPSC-derived neurons

“…A second set of enriched pathways consisted of DNA damage pathways, including "UVB/C-induced MAPK signaling", "ATM signaling", and "p53 signaling". Recently, we have shown that several synaptic pathways are impaired in the hippocampus of AD patients by analyzing transcriptomic data and have also linked these findings to somatic DNA damage (Soheili-Nezhad et al, 2021). In this respect, an impaired p53-mediated DNA damage response has been observed in AD patient brains (Farmer et al, 2020).…”