{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T23:11:02Z","timestamp":1792019462889,"version":"4.4.0"},"reference-count":58,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T00:00:00Z","timestamp":1771372800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"NHMRC-ARC dementia research development","doi-asserted-by":"publisher","award":["APP1107109"],"award-info":[{"award-number":["APP1107109"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NFMRI (National Foundation for Medical Research and Innovation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Dysregulation of the deubiquitinating enzyme Ubiquitin-specific peptidase 14 (USP14) is implicated in several neurodegenerative diseases, and IU1, an allosteric inhibitor, has shown neuroprotective effects by reducing protein aggregate toxicity. This study aimed to develop new IU1 analogues and evaluate their ability to mitigate amyloid-\u03b2 (A\u03b2) accumulation and toxicity in Alzheimer\u2019s disease (AD) cell and Caenorhabditis elegans worm models. IU1 and 71 newly designed analogues identified using the AtomNet\u00ae virtual screening platform were assessed in an amyloid precursor protein-C terminal fragment\/amyloid-\u03b2 (APP-C99\/A\u03b2)-producing AD cell model using a high-throughput toxicity assay. Lead compounds were further evaluated for their effects on neurodegeneration, behaviour, and survival. IU1 reduced A\u03b2-mediated toxicity and neurodegeneration in cell and worm models. Of the 71 analogues predicted to bind ubiquitin-specific peptidase 14 (USP14), two compounds, AA10 and AA51, showed &gt;50% rescue of A\u03b2-induced toxicity and robust enhancement of autophagy and proteasome activity. In Caenorhabditis elegans, both compounds alleviated glutamatergic neuron loss and rescued behavioural impairments. IU1 and analogues exhibit protective effects against A\u03b2 toxicity in AD models. Analogues AA10 and AA51 showed greater potency than IU1 and effectively enhanced proteostasis pathways. These findings support USP14 as a promising therapeutic target and provide a basis for the development of improved IU1-derived compounds for AD and related disorders.<\/jats:p>","DOI":"10.3390\/ijms27041963","type":"journal-article","created":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T15:28:18Z","timestamp":1771428498000},"page":"1963","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Novel Small-Molecule Analogues of IU1 Ameliorate Amyloid-\u03b2 Mediated Toxicity in Alzheimer\u2019s Disease Cell and Worm Models"],"prefix":"10.3390","volume":"27","author":[{"given":"Ajish","family":"Ariyath","sequence":"first","affiliation":[{"name":"Centre of Excellence for Alzheimer\u2019s Disease Research and Care, School of Medical and Health Sciences, Sarich and Patricia Neuroscience Research Institute, Edith Cowan University, Joondalup, WA 6027, Australia"},{"name":"Alzheimer\u2019s Research Australia, Nedlands, WA 6009, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5169-0199","authenticated-orcid":false,"given":"Fraulein Denise","family":"Arigo","sequence":"additional","affiliation":[{"name":"Centre of Excellence for Alzheimer\u2019s Disease Research and Care, School of Medical and Health Sciences, Sarich and Patricia Neuroscience Research Institute, Edith Cowan University, Joondalup, WA 6027, Australia"},{"name":"Alzheimer\u2019s Research Australia, Nedlands, WA 6009, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Izhar","family":"Wallach","sequence":"additional","affiliation":[{"name":"Atomwise, 250 Sutter St, Suite 650, San Francisco, CA 94108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. M. A. D. Binosha","family":"Fernando","sequence":"additional","affiliation":[{"name":"Centre of Excellence for Alzheimer\u2019s Disease Research and Care, School of Medical and Health Sciences, Sarich and Patricia Neuroscience Research Institute, Edith Cowan University, Joondalup, WA 6027, Australia"},{"name":"Alzheimer\u2019s Research Australia, Nedlands, WA 6009, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph N.","family":"Martins","sequence":"additional","affiliation":[{"name":"Centre of Excellence for Alzheimer\u2019s Disease Research and Care, School of Medical and Health Sciences, Sarich and Patricia Neuroscience Research Institute, Edith Cowan University, Joondalup, WA 6027, Australia"},{"name":"Alzheimer\u2019s Research Australia, Nedlands, WA 6009, Australia"},{"name":"School of Biomedical Science, Macquarie University, Sydney, NSW 2109, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4361-9906","authenticated-orcid":false,"given":"Prashant","family":"Bharadwaj","sequence":"additional","affiliation":[{"name":"Centre of Excellence for Alzheimer\u2019s Disease Research and Care, School of Medical and Health Sciences, Sarich and Patricia Neuroscience Research Institute, Edith Cowan University, Joondalup, WA 6027, Australia"},{"name":"Alzheimer\u2019s Research Australia, Nedlands, WA 6009, Australia"},{"name":"Curtin Medical School, Curtin Health and Innovation Research Institute (CHIRI), Faculty of Health Sciences, Curtin University, Perth, WA 6107, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3234","DOI":"10.1212\/WNL.0000000000205009","article-title":"Projected Global Burden of Brain Disorders Through 2050 (P7-15.001)","volume":"102","author":"Lei","year":"2024","journal-title":"Neurology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/S1474-4422(19)30411-9","article-title":"The global burden of neurological disorders: Translating evidence into policy","volume":"19","author":"Feigin","year":"2020","journal-title":"Lancet Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e70048","DOI":"10.1002\/alz.70048","article-title":"Tau degradation in Alzheimer\u2019s disease: Mechanisms and therapeutic opportunities","volume":"21","author":"Wang","year":"2025","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Dantuma, N.P., and Bott, L.C. 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