Biology subjects

Marsh, T.

Publications and source records attributed to Marsh, T..

3 recordsLinked to original sources

bioRxiv2026

The NORAD-pumilio regulatory axis links lncRNA dysregulation to tau propagation-associated phenotypes

Long non-coding RNAs (lncRNAs) are increasingly implicated in neurodegenerative disease, yet their roles in tauopathy remain poorly understood. Here, we defined the lncRNA landscape across iPSC-derived neurons, astrocytes, and microglia harboring the frontotemporal dementia-associated MAPT IVS10+16 mutation and investigated how lncRNA dysregulation interfaces with tau pathology. Transcriptomic analyses revealed extensive cell-type specific lncRNA expression changes, with neurons exhibiting the greatest degree of mutation-associated remodeling. Comparative analyses with MAPT IVS10+16 patient brain tissue identified NORAD and MIR22HG as lncRNAs significantly dysregulated across all three cell types and human brains. NORAD was also altered in Alzheimers disease and Parkinsons disease brains, suggesting a broader role in neurodegenerative disease. Mechanistically, NORAD-associated protein networks converged on pathways related to RNA regulation, cytoskeletal organization, proteostasis, and tau interaction networks. Given the established role of NORAD in regulating PUM1 and PUM2 RNA-binding (pumilio) proteins, we examined the NORAD-pumilio axis and identified enrichment of pumilio-associated pathways linked to autophagy, endocytosis, proteostasis, and cytoskeletal regulation. NORAD depletion reduced tau seeding and uptake, whereas functional depletion of PUM1 or PUM2 increased both processes, supporting an antagonistic relationship between NORAD and pumilio signaling in modulation of tau aggregation. Together, these findings identify widespread lncRNA dysregulation across neural cell types in the setting of a MAPT mutation and nominate the NORAD-pumilio axis as a regulatory pathway linking RNA homeostasis and tau propagation biology.

neuroscience↗

bioRxiv2021

Autophagy cargo receptors are secreted via extracellular vesicles and particles in response to endolysosomal inhibition or impaired autophagosome maturation

The endosome-lysosome (endolysosome) system plays central roles in both autophagic degradation and secretory pathways, including the exocytic release of extracellular vesicles and particles (EVPs). Although previous work has revealed important interconnections between autophagy and EVP-mediated secretion, our molecular understanding of these secretory events during endolysosome inhibition remains incomplete. Here, we delineate a secretory autophagy pathway upregulated in response to endolysosomal inhibition that mediates the EVP-associated extracellular release of autophagic cargo receptors, including p62/SQSTM1. This extracellular secretion is highly regulated and critically dependent on multiple ATGs required for the progressive steps of early autophagosome formation as well as Rab27a-dependent exocytosis. Furthermore, the disruption of autophagosome maturation, either due to genetic inhibition of the autophagosome-to-autolyosome fusion machinery or blockade via the SARS-CoV2 viral protein ORF3a, is sufficient to induce robust EVP-associated secretion of autophagy cargo receptors. Finally, we demonstrate that this ATG-dependent, EVP-mediated secretion pathway buffers against the intracellular accumulation of autophagy cargo receptors when classical autophagic degradation is impaired. Based on these results, we propose that secretory autophagy via EVPs functions as an alternate route to clear sequestered material and maintain proteostasis in response to endolysosomal dysfunction or impaired autophagosome maturation.

cell biology↗

bioRxiv2019

Genome annotation of Poly(lactic acid) degrading Pseudomonas aeruginosa and Sphingobacterium sp.

Pseudomonas aeruginosa and Sphinogobacterium sp. are well known for their ability to decontaminate many environmental pollutants like PAHs, dyes, pesticides and plastics. The present study reports the annotation of genomes from P. aeruginosa and Sphinogobacterium sp. that were isolated from compost, based on their ability to degrade poly(lactic acid), PLA, at mesophillic temperatures (~30{degrees}C). Draft genomes of both the strains were assembled from Illumina reads, annotated and viewed with an aim of gaining insight into the genetic elements involved in degradation of PLA. The draft-assembled genome of strain Sphinogobacterium strain S2 was 5,604,691 bp in length with 435 contigs (maximum length of 434,971 bp) and an average G+C content of 43.5%. The assembled genome of P. aeruginosa strain S3 was 6,631,638 bp long with 303 contigs (maximum contig length of 659,181 bp) and an average G+C content 66.17 %. A total of 5,385 (60% with annotation) and 6,437 (80% with annotation) protein-coding genes were predicted for strains S2 and S3 respectively. Catabolic genes for biodegradation of xenobiotic and aromatic compounds were identified on both draft genomes. Both strains were found to have the genes attributable to the establishment and regulation of biofilm, with more extensive annotation for this in S3. The genome of P. aeruginosa S3 had the complete cascade of genes involved in the transport and utilization of lactate while Sphinogobacterium strain S2 lacked lactate permease, consistent with its inability to grow on lactate. As a whole, our results reveal and predict the genetic elements providing both strains with the ability to degrade PLA at mesophilic temperature.

microbiology↗