Ataxia-Telangiectasia (A-T) is caused by biallelic Ataxia-Telangiectasia Mutated (ATM) protein mutations and is hallmarked by neurodegeneration, immunodeficiency and cancer susceptibility. Emerging work suggests that non-coding RNAs are integral to the ATM driven DNA damage response, yet the scope of non-coding RNA perturbation in A-T has not systematically mapped. This study is done to chart and synthesize all primary evidence on ncRNA dysregulation in A-T and to identify mechanistic gaps and research priorities. The evidence base comprises a total of five studies focused exclusively on microRNAs and long non-coding RNAs. Baseline sequencing of 20 patients revealed consistent downregulation of miR-195-5p, miR-30a-5p and miR-342-3p. Low dose γ-irradiation of ATM-null lymphoblastoid cell lines produced an exaggerated bidirectional shift (8 microRNAs upregulated, 6 downregulated) versus wild-type, whereas primary T-cells showed largely ATM independent rises of miR-34a-5p and miR-182-5p. A lymphoblastoid cell lines study distinguished 22 recessive or dominant radiation-responsive microRNAs. Long non-coding RNAs profiling identified 149 transcripts that require functional ATM for induction and three uniquely upregulated in A-T cells. No circular RNA study in A-T is observed till date. The ncRNA research in A-T is nascent with five studies present a miRNA dysregulation and an ATM-dependent lncRNA surge that is lost in A-T, but leave circRNAs, neuronal tissues and functional validation unexplored. Intermediate dose stress models, total and small RNA-seq under DNA damage and oxidative stress, and CRISPR rescue/knockout screens in patient derived organoids are immediate priorities for exploring the role of ncRNAs as therapeutic targets in A-T.

Background: Ataxia-telangiectasia (A-T) is a rare autosomal recessive genome-instability disorder due to pathogenic variants in ATM, a central kinase of the DNA double-strand break signaling, checkpoint activation and stress-response pathways. Although microRNAs (miRNAs) regulate DNA damage response (DDR), apoptosis, senescence and cell-cycle control, the stress-responsive behavior of selected ATM/DDR-associated miRNAs remains incompletely characterized in A-T fibroblast models. Methods and Results: Four predefined ATM/DDR-associated candidate miRNAs (hsa-miR-34a-5p, hsa-miR-26a-5p, hsa-miR-106b-5p and hsa-miR-20a-5p) were quantified in one ATM-proficient fibroblast control and three A-T fibroblast cell lines both under basal and bleomycin exposed conditions. The relative expression of selected miRNAs was measured by RT-qPCR. miR-34a-5p and miR-26a-5p levels were lower in each of the three bleomycin-treated A-T lines relative to the single bleomycin-treated WT control line. miR-34a-5p and miR-26a-5p levels were lower in bleomycin-treated three A-T lines relative to the single control WT line. Within-cell-line analysis showed significant miR-34a-5p induction after bleomycin in WT, AT648 and AT9607, whereas significant miR-26a-5p induction was observed only in AT648. AT648 showed the broadest within-cell-line response, with significant induction of all four tested miRNAs after bleomycin. Target-based enrichment and network analyses of the predefined candidate panel identified annotations related to cell-cycle regulation, G1/S transition, RB/E2F signaling, p53 signaling, apoptosis, senescence, PI3K-Akt signaling, and DNA damage-associated processes. Network analysis revealed a number of shared candidate targets such as CCND1 , CCND2 , E2F1 , E2F3 , RB1 , WEE1 , PTEN , SMAD4 , MYC and VEGFA . Conclusions: In this fibroblast panel, miR-34a-5p and miR-26a-5p showed the most consistent baseline alterations, whereas bleomycin responsiveness was cell-line specific and heterogeneous.

Ataxia-telangiectasia arises from loss of ATM kinase function, precipitating genomic instability, oxidative stress, neurodegeneration, and metabolic dysregulation. While compact ATM variants have been proposed for gene replacement, their capacity to restore the biochemical homeostasis disrupted by ATM deficiency remains incompletely defined. Here we performed an integrated metabolomic, ¹³C isotopologue, and proteomic analysis of AT fibroblasts transduced with ATM4-53 or ATM-SINT, using wild-type fibroblasts as reference. Untargeted metabolomics revealed extensive biochemical remodeling in AT cells, with 240 metabolites significantly altered. Perturbation coherently involved nucleotide metabolism, glutathione and oxidative stress pathways, central carbon metabolism, and critical energy indices, highlighted by elevated AMP/ATP and ADP/ATP ratios and a marked decline in cellular energy charge. Both compact variants modulated the AT metabolic phenotype, yet through distinct profiles: ATM4-53 elicited a broad, rescue-like response attenuating multiple AT-associated abnormalities, whereas ATM-SINT produced a heterogeneous profile retaining nucleotide and biosynthetic signatures. Proteomic analysis of 7,036 unique protein accessions confirmed widespread molecular remodeling. Multi-omics integration indicated that ATM deficiency dictates systematic rewiring rather than isolated shifts: ATM4-53 preferentially attenuated redox, NAD-linked redox, and TCA-pyruvate modules, while ATM-SINT suppressed select ATP phosphotransferase, phosphoinositide, and adenosine-associated modules yet preserved distinct nucleotide and redox signatures. Seahorse XF bioenergetic analysis supported these findings, showing altered ATP production balance and substrate dependency in compact ATM expressing cells. Collectively, compact ATM variants are not functionally equivalent at the biochemical network level. This framework provides a mechanistic basis for evaluating compact ATM replacement strategies and delineating construct-specific biochemical responses in AT.

Ataxia-telangiectasia (A-T) is a multisystemic genetic disorder caused by pathogenic mutations in the ATM gene, with effects extending beyond the canonical DNA damage response. We investigated whether two compact ATM transcript variants, ATM 4-53 (exons 4 and 53 joined) and ATM SINT (an in silico-designed ATM variant), could rescue disease associated with cellular alterations and inform construct selection for future delivery strategies. A-T fibroblasts transduced with either ATM variants or an empty vector were compared with wild-type fibroblasts using complementary label-free and tandem mass tag-based quantitative proteomics. Bioinformatic pathway and network analyses were integrated with biochemical and functional validation assays. A-T fibroblasts displayed coordinated alterations in proteostasis, proteasome function, RNA processing pathways, interferon-associated signaling, extracellular matrix organization, cell migration, and nanomechanical properties. Expression of both ATM variants partially or extensively reversed these abnormalities, restoring protein folding and proteasomal components, reducing protein aggregation, attenuating inflammatory signaling, and normalizing extracellular matrix-related phenotypes. ATM SINT generally produced the broader and more consistent rescue, particularly for proteostasis and RNA processing-associated networks. These findings show that compact ATM variants can recover multiple non canonical ATM dependent cellular functions in A-T fibroblasts and identify ATM SINT as the more effective construct in this model. Proteomic profiling combined with orthogonal functional validation may therefore support rational selection of ATM variants for subsequent preclinical delivery studies.

Hereditary ataxias are rare cerebellar disorders. Population level mortality patterns in the United States in the previous decades remain insufficiently described. We quantified national mortality trends associated with hereditary ataxias and described stratified trends by sex, race, census region, and urbanization. We analyzed U.S. Multiple Cause of Death data from CDC WONDER for 2000 to 2020. Decedents were identified using ICD-10 code G11 for hereditary ataxias. Age-adjusted mortality rates (AAMRs) per 100,000 were computed using the 2000 U.S. standard population, with 95% confidence intervals. Temporal trends were evaluated using joinpoint regression to estimate annual percent change (APC). Forecasts through 2050 were generated using ARIMA, with sensitivity analysis using linear regression. National AAMR increased significantly from 2000 to 2020. Rising rates were observed in both sexes, with consistently higher mortality among males. The largest relative increases occurred among Black or African American individuals and in the West census region. Trends were directionally consistent across urbanization categories, and the forecast analyses also indicated increasing overall mortality. Sensitivity analyses produced qualitatively similar patterns, with wider uncertainty within strata. Mortality associated with hereditary ataxias increased in the United States between 2000 and 2020, highlighting growing clinical and public health needs related to cerebellar disease. Improved phenotyping and coding, earlier diagnosis, and registry-linked surveillance may refine estimates and support service planning. Graphical Abstract Mortality associated with hereditary ataxias increased in the United States from 2000 to 2020. National AAMR rose significantly over 2000 to 2020. Increases occurred in both sexes, with consistently higher rates among males. The largest relative increases were observed among Black or African American individuals and in the West census region. Patterns were directionally consistent across urbanization categories, and the forecast analysis also showed increasing mortality