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In affected patients, cytoplasmic TDP-43 aggregates are accompanied by disruption of its normal nuclear localization and function. Because TDP-43 is an RNA binding protein that controls transcript processing, including repression of cryptic exon splicing, its loss leads to dysregulation of gene expression. Despite its central significance in disease, the connection between TDP-43 aggregation and dysfunction remains poorly understood, and models to study the underlying mechanisms are limited. Here, we characterize a robust and quantitative cell-based reporter that captures both aggregation and the resulting loss of function. Using this human biosensor cell line, we show that aggregation initiated by prion-like seeding drives progressive depletion of nuclear TDP-43 and induces signature features of diminished TDP-43 activity, such as increased DNA damage and activation of cryptic exon splicing. We find that aggregate seeding also induces cryptic exon splicing in human neurons implying that this pathological link extends to disease-relevant models. The seeding model provides a platform for dissecting mechanisms that underlie TDP-43 pathology and for identifying factors that modulate the aggregation-to-dysfunction transition. Our data shows that aggregate seeding impacts TDP-43 autoregulation, initiating a toxic feed-forward mechanism that disrupts TDP-43 homeostasis. Furthermore, reducing ataxin-2 levels decreases aggregation and restores TDP-43 activity. Together, these findings reveal a molecularly guided strategy to directly impact TDP-43 activity by decreasing its misfolding and aggregation, highlighting approaches to prevent TDP-43 dysfunction and mitigate toxicity under pathological conditions.<\/jats:p>","DOI":"10.1371\/journal.pbio.3003662","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T17:21:37Z","timestamp":1774372897000},"page":"e3003662","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["A quantitative cell-based reporter links TDP-43 aggregation and dysfunction to define pathogenic mechanisms"],"prefix":"10.1371","volume":"24","author":[{"given":"Lohany 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