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Using molecular and imaging techniques, we have identified a novel role for the Fragile X Mental Retardation Protein (FMRP) in regulating the TNKS\/PI31\u2010mediated proteasome activation mechanism in co\u2010operation with TDP\u201043. Our results demonstrate that depletion of FMRP causes nuclear translocation of TDP\u201043, reducing cytoplasmic TNKS\/TDP\u201043 co\u2010localization, thereby releasing TNKS in the cytoplasm. Free TNKS gets associated with proteasome inhibitor of 31\u2009kDa (PI31), reversing PI31\u2010mediated inhibition of proteasome assembly, trafficking, and activity. Thus, FMRP regulates proteasome activity by modulating the subcellular distribution of TDP\u201043. Interestingly, FMRP expression is elevated in specific brain regions and spinal cords of TDP\u201043\n                    <jats:sup>A315T<\/jats:sup>\n                    transgenic ALS mice that helps more TDP\u201043 to stay in cytoplasm to sequester more TNKS with it, resulting in proteasome dysfunction in ALS disease system. We have demonstrated for the first time that FMRP can act as a disease modifier for ALS. ALS patients with high FMRP expression in the brain and spinal cord may exhibit more severe protein aggregation due to proteasome dysfunction.\n                  <\/jats:p>","DOI":"10.1096\/fj.202600563r","type":"journal-article","created":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T07:50:08Z","timestamp":1782546608000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["<scp>FMRP<\/scp>\n                    \u2010Mediated Proteasome Regulation: A Novel Mechanism in\n                    <scp>ALS<\/scp>\n                    Pathology"],"prefix":"10.1096","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-4366-8612","authenticated-orcid":false,"given":"Pritha","family":"Majumder","sequence":"first","affiliation":[{"name":"PhD Program in Medical Neuroscience, College of Medical Science and Technology Taipei Medical University, Shuang\u2010Ho Campus  New Taipei City Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asmar","family":"Ahsan","sequence":"additional","affiliation":[{"name":"PhD Program in Medical Neuroscience, College of Medical Science and Technology Taipei Medical University, Shuang\u2010Ho Campus  New Taipei City Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pitchapa","family":"Bubphachat","sequence":"additional","affiliation":[{"name":"PhD Program in Medical Neuroscience, College of Medical Science and Technology Taipei Medical University, Shuang\u2010Ho Campus  New Taipei City Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khadiza","family":"Akter","sequence":"additional","affiliation":[{"name":"PhD Program in Medical Neuroscience, College of Medical Science and Technology Taipei Medical University, Shuang\u2010Ho Campus  New Taipei City Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey K.","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Biology Georgetown University  Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5410-8285","authenticated-orcid":false,"given":"Chi\u2010Chen Sarah","family":"Huang","sequence":"additional","affiliation":[{"name":"PhD Program in Medical Neuroscience, College of Medical Science and Technology Taipei Medical University, Shuang\u2010Ho Campus  New Taipei City Taiwan"},{"name":"International Master Program in Medical Neuroscience, College of Medical Science and Technology Taipei Medical University, Shuang\u2010Ho Campus  New Taipei City Taiwan"},{"name":"School of Medicine, College of Medicine Taipei Medical University, Shuang\u2010Ho Campus  New Taipei City Taiwan"},{"name":"TMU Research Center for Neuroscience Taipei Medical University, Shuang\u2010Ho Campus  New Taipei City Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,27]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41576\u2010023\u201000592\u2010y"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mad.2018.03.005"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells13110967"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a024117"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/ene.14393"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.3109\/21678421.2013.778548"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/120.10.1723"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2011.150"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/8413496"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2022.826719"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2020.101700"},{"key":"e_1_2_13_13_1","doi-asserted-by":"crossref","unstructured":"M.Neumann D. 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