Anastasiia Lovchykova

All Publications

• TDP-43-mediated alternative polyadenylation is associated with a reduction in VPS35 and VPS29 expression in frontotemporal dementia. PLoS biology Maheswari Jawahar, V., Zeng, Y., Armour, E. M., Yue, M., Citrano, K., Lovchykova, A., Reeves, M. M., Rawlinson, B., DeTure, M., Dunmore, J. A., Song, Y., Ball, S. K., Wszolek, Z. K., Graff-Radford, N. R., Boeve, B. F., Knopman, D. S., Day, G. S., Small, S. A., Dickson, D. W., Ward, M. E., Gendron, T. F., Zhang, Y., Prudencio, M., Gitler, A. D., Petrucelli, L. 2026; 24 (1): e3003573

  Abstract

  TAR DNA-binding protein 43 (TDP-43) dysfunction is a hallmark of several neurodegenerative diseases, including frontotemporal dementia, amyotrophic lateral sclerosis, and Alzheimer's disease. Although cryptic exon inclusion is a well-characterized consequence of TDP-43 loss of function, emerging evidence reveals broader roles in RNA metabolism, notably in the regulation of alternative polyadenylation (APA) of disease-relevant transcripts. In the present study, we examined 3' untranslated region lengthening events in the brains of individuals with frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), focusing on the functional impact of APA dysregulation. To investigate whether TDP-43-mediated APA events occur in the postmortem brain, we measured the 3' untranslated region length of the retromer component vacuolar protein sorting 35 (VPS35) and the ETS transcription factor (ELK1) in the frontal cortex of a large cohort of FTLD-TDP patients and of healthy controls, and evaluated if these APA events are associated with FTLD-TDP clinical characteristic, markers of TDP-43 pathology [e.g., hyperphosphorylated TDP-43 and cryptic stathmin-2 RNA], or the expression of VPS35 and VPS29 proteins, the latter being essential to the retromer complex. We identified robust 3' untranslated region lengthening of VPS35 and ELK1 in FTLD-TDP, which strongly associated with markers of TDP-43 pathology, and ELK1 APA also associated with an earlier age of disease onset. Functionally, VPS35 APA was associated with reduced VPS35 and VPS29 protein expression, and lower VPS35 levels were associated with increased hyperphosphorylated TDP-43 and cryptic stathmin-2 RNA. Together, these data implicate APA dysregulation as a critical downstream consequence of TDP-43 dysfunction and suggest that TDP-43 loss may contribute to retromer impairment through APA-mediated repression of retromer subunits.

  View details for DOI 10.1371/journal.pbio.3003573

  View details for PubMedID 41490046

• TDP-43 nuclear loss in FTD/ALS causes widespread alternative polyadenylation changes. Nature neuroscience Zeng, Y., Lovchykova, A., Akiyama, T., Rayner, S. L., Maheswari Jawahar, V., Liu, C., Sianto, O., Guo, C., Calliari, A., Prudencio, M., Dickson, D. W., Petrucelli, L., Gitler, A. D. 2025

  Abstract

  In frontotemporal dementia and amyotrophic lateral sclerosis, the RNA-binding protein TDP-43 is depleted from the nucleus of neurons in the brain and spinal cord. A key function of TDP-43 has emerged as a repressor of cryptic exon inclusion during pre-mRNA splicing, but a role for TDP-43 in other RNA-processing events remains unresolved. Here we show that loss of TDP-43 from neuronal nuclei of human brain and disease-causing mutations in TDP-43 are associated with widespread changes in alternative polyadenylation (APA). Using high-resolution polyadenylation site mapping, we comprehensively defined TDP-43-regulated APA events in human stem cell-derived neurons and found that both the strength and position of TDP-43 binding influence polyA site usage. APA events caused by loss of TDP-43 impact expression of disease-relevant genes (for example, SFPQ, NEFL and TMEM106B). These findings provide evidence that, in addition to cryptic exon inclusion, APA changes are a new facet of TDP-43 pathology.

  View details for DOI 10.1038/s41593-025-02049-3

  View details for PubMedID 41120750

  View details for PubMedCentralID 3108889

• Nonsense-mediated decay masks cryptic splicing events caused by TDP-43 loss. bioRxiv : the preprint server for biology Zeng, Y., Sianto, O., Lovchykova, A., Liu, C., Akiyama, T., Petrucelli, L., Gitler, A. D. 2025

  Abstract

  In frontotemporal dementia and amyotrophic lateral sclerosis, the RNA-binding protein TDP-43 is lost from the nucleus, leading to cryptic exon inclusion events in dozens of neuronal genes. Here, we show that many cryptic splicing events have been missed by standard RNA-sequencing analyses because they are substrates for nonsense-mediated decay. By inhibiting nonsense-mediated decay in neurons we unmask hundreds of novel cryptic splicing events caused by TDP-43 depletion, providing a new picture to TDP-43 loss of function in neurons.

  View details for DOI 10.1101/2025.07.09.664014

  View details for PubMedID 40672339

  View details for PubMedCentralID PMC12265704

• TDP-43 nuclear loss in FTD/ALS causes widespread alternative polyadenylation changes. bioRxiv : the preprint server for biology Zeng, Y., Lovchykova, A., Akiyama, T., Liu, C., Guo, C., Jawahar, V. M., Sianto, O., Calliari, A., Prudencio, M., Dickson, D. W., Petrucelli, L., Gitler, A. D. 2024

  Abstract

  In frontotemporal dementia and amyotrophic lateral sclerosis, the RNA-binding protein TDP-43 is depleted from the nucleus. TDP-43 loss leads to cryptic exon inclusion but a role in other RNA processing events remains unresolved. Here, we show that loss of TDP-43 causes widespread changes in alternative polyadenylation, impacting expression of disease-relevant genes (e.g., ELP1, NEFL, and TMEM106B) and providing evidence that alternative polyadenylation is a new facet of TDP-43 pathology.

  View details for DOI 10.1101/2024.01.22.575730

  View details for PubMedID 38328059

  View details for PubMedCentralID PMC10849503