{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T09:24:48Z","timestamp":1787649888788,"version":"build-2736575974"},"reference-count":92,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"AMED","doi-asserted-by":"publisher","award":["JP26dk0207077"],"award-info":[{"award-number":["JP26dk0207077"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Jpeaks","award":["JPJS00420240024"],"award-info":[{"award-number":["JPJS00420240024"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>TDP-43 proteinopathies, encompassing amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and limbic-predominant age-related TDP-43 encephalopathy (LATE), represent a heterogeneous spectrum of devastating neurodegenerative disorders. For decades, the diverse clinical presentations of these diseases have complicated antemortem diagnosis and hindered the development of disease-modifying therapies. However, recent breakthroughs in basic science are beginning to address these clinical barriers, although substantial hurdles to practical clinical application remain. Structural elucidation via cryo-electron microscopy (Cryo-EM) has shattered the single-protein amyloid dogma by revealing that TDP-43 can form hetero-amyloid filaments with ANXA11, thereby providing a molecular basis for pathological strain diversity. Concurrently, the pathogenic focus has shifted toward nuclear loss of function, which triggers a systemic \u201cRNA crisis\u201d characterized by aberrant alternative polyadenylation (APA) and cryptic exon inclusion (e.g., STMN2, UNC13A). Crucially, this metabolic collapse is profoundly exacerbated by patient-specific genetic risk factors, acting synergistically in a \u201ctwo-hit\u201d model of neurodegeneration. To translate these findings to the clinic, next-generation diagnostic tools are emerging. Integrating neuron-derived extracellular vesicle (EV) isolation with Seed Amplification Assays (SAAs) holds promise to help overcome the structural camouflage that limits current PET imaging, potentially offering ultra-sensitive, functional strain identification in biofluids. While these structural and diagnostic milestones provide a strong foundation for precision medicine, major challenges in assay standardization and clinical validation must be addressed. Advanced therapeutic strategies\u2014namely, splice-switching antisense oligonucleotides (ASOs) that directly restore RNA metabolism, combined with the targeted suppression of neuronal hyperexcitability\u2014are now entering clinical trials. This review synthesizes how decoding the structural and RNA-metabolic complexities of TDP-43 is paving a promising pathway from bench to bedside, while critically discussing current translational limitations.<\/jats:p>","DOI":"10.3390\/pathogens15090890","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T09:04:30Z","timestamp":1787648670000},"page":"890","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Prion-like Protein TDP-43: Mechanisms, Diagnosis, and Therapeutic Prospects"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3830-2173","authenticated-orcid":false,"given":"Mika Inada","family":"Shimamura","sequence":"first","affiliation":[{"name":"Department of Health Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan"},{"name":"Multidisciplinary Pandemic Research Center, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8588, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8007-8710","authenticated-orcid":false,"given":"Katsuya","family":"Satoh","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan"},{"name":"Multidisciplinary Pandemic Research Center, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8588, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1038\/emboj.2010.310","article-title":"TDP-43 regulates its mRNA levels through a negative feedback loop","volume":"30","author":"Ayala","year":"2011","journal-title":"EMBO J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"36337","DOI":"10.1074\/jbc.M104236200","article-title":"Characterization and functional implications of the RNA binding properties of nuclear factor TDP-43, a novel splicing regulator of CFTR exon 9","volume":"276","author":"Buratti","year":"2001","journal-title":"J. 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