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TAR DNA-binding protein (TDP-43) and Metastasis Associated Lung Adenocarcinoma Transcript (MALAT1) RNA are both abundantly expressed in the human cell nucleus. Increased interaction of TDP-43 and MALAT1, as well as dysregulation of TDP-43 function, was previously identified in brain samples from patients with neurodegenerative disease compared to healthy brain tissues. We hypothesized that TDP-43 function may depend in part on MALAT1 expression levels. Here, we find that alterations in MALAT1 expression affect cell viability and can modulate TDP-43 binding to other mRNAs in HEK293 and SH-SH5Y human cell lines. Disruption of either MALAT1 or TDP-43 expression induces cell death, indicating that both macromolecules contribute positively to survival. Depletion of MALAT1 RNA results in increased binding of TDP-43 to other mRNA transcripts at the 3' UTR. Finally, we examined the contribution of MALAT1 expression to survival in a cell culture model of neurodegeneration using MPP + treatment in SH-SY5Y cells. Depletion of MALAT1 RNA protects against toxicity in a cellular model of neurodegeneration and modulates TDP-43 binding to mRNA transcripts involved in apoptotic cell death. Taken together, we find that MALAT1 RNA and TDP-43 interactions can affect mRNA levels and cell viability. A tightly regulated network of non-coding RNA, messenger RNA, and protein interactions could provide a mechanism to maintain appropriate RNA expression levels and contribute to neuronal function., Competing Interests: Conflicts of Interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)