{
  "abstract": "Mislocalization and aggregation of the RNA-binding proteins (RBPs) FUS and TDP-43 are pathological hallmarks of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), contributing to combined loss- and gain-of-function toxicity. Here, we present a protein engineering strategy that appends optimized anti-aggregation motifs to FUS and TDP-43, thereby enhancing their nuclear localization and solubility, and enabling functional replacement of disease-associated proteins. We show that these engineered chimeric RBPs reduce levels of aggregation-prone endogenous proteins through autoregulatory mechanisms. In addition, chimeric FUS and TDP-43 recapitulate key nuclear functions, including DNA repair and mRNA processing. Notably, chimeric FUS restores neurite outgrowth in diseased iPSC-derived neurons, while chimeric TDP-43 suppresses cryptic exon inclusion in patient-derived fibroblasts. Collectively, these results demonstrate that engineered chimeric RBPs can rebalance RBP homeostasis by simultaneously addressing protein aggregation and mislocalization, thus mitigating RBP-associated loss- and gain-of-function toxicity, highlighting a generalizable strategy for therapeutic protein replacement in neurodegenerative disease.",
  "abstract_shown": true,
  "affiliations": [
    "Thomas Jefferson University"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 13,
  "authors": [
    {
      "name": "M. Hayashi"
    },
    {
      "name": "B. K. Jensen"
    },
    {
      "name": "A. Girdhar"
    },
    {
      "name": "S. S. Markandaiah"
    },
    {
      "name": "Y.-H. Ko"
    },
    {
      "name": "N. Arunprakash"
    },
    {
      "name": "J. A. DePierro"
    },
    {
      "name": "T. Ni"
    },
    {
      "name": "W. Li"
    },
    {
      "name": "W. Zhao"
    },
    {
      "name": "G. Cingolani"
    },
    {
      "name": "P. Pasinelli"
    },
    {
      "affs": [
        0
      ],
      "name": "L. Guo"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/dft4vvnk8mbch.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.28.755047",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.28.755047v1.full",
  "id": "dft4vvnk8mbch",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.28.755047v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "neuroscience"
    ],
    [
      "openalex",
      "2728|Amyotrophic Lateral Sclerosis Research"
    ]
  ],
  "openalex": "W7218508860",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.28.755047v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-28",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/dft4vvnk8mbch.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:26:37Z",
      "native_id": "10.64898/2026.09.28.755047",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.28.755047v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:neuroscience",
      "subfield": "neuroscience"
    }
  ],
  "title": "Engineered Chimeric Proteins Functionally Replace ALS-causing Endogenous FUS and TDP-43 to Improve Neuronal Health",
  "title_text": "Engineered Chimeric Proteins Functionally Replace ALS-causing Endogenous FUS and TDP-43 to Improve Neuronal Health",
  "type": "preprint",
  "updated_at": "2026-10-30T12:26:37Z",
  "url": "https://research.draconitic.com/paper/dft4vvnk8mbch",
  "venue": "bioRxiv",
  "versions": []
}