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Although transcriptomic and proteomic changes have been characterized in patient-derived neurons, the contribution of post-translational modifications, such as phosphorylation, remains poorly understood. Here, we present the first phosphoproteomic analysis by mass spectrometry (P-MS) of human induced neurons (iNs) directly reprogrammed from HD patient fibroblasts. We identified 177 phosphopeptides with significantly altered abundance in HD-iNs, mapping to phosphoproteins associated with key signaling pathways known to be affected in HD, such as splicing and autophagy. By integrating P-MS data with previously published proteomic and transcriptomic data from the same donors, we identified distinct subsets of ON\u2013OFF phosphopeptides that exhibited a complete loss of phosphorylation in either HD- or control-iNs, without corresponding changes at the RNA or protein level. An exception was MXRA8, previously described in glial cells as a mediator of blood\u2013brain barrier integrity and astrocyte-mediated neuroinflammation. This protein showed increased protein abundance despite the absence of phosphorylation in HD-iNs, suggesting a compensatory mechanism. In addition, MXRA8 showed altered protein\u2013protein interactions with lysosomal and metabolic regulators in HD-iNs, highlighting its potential role in autophagy impairment as well as in neurovascular dysfunction. These findings uncover a distinct layer of post-translational dysregulation in HD, suggesting that phospho-switch proteins such as MXRA8 may be candidate effectors of pathology, and thus, site-specific phosphorylation loss may contribute to impaired signaling and proteostasis in human HD neurons.\n                  <\/jats:p>","DOI":"10.1186\/s11658-026-00948-2","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T21:07:24Z","timestamp":1780434444000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Phosphoproteomic profiling reveals post-translational dysregulation in Huntington\u2019s disease patient-derived neurons"],"prefix":"10.1186","volume":"31","author":[{"given":"Lea","family":"Danics","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandramouli","family":"Muralidharan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1gnes","family":"Varga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melinda","family":"Rezeli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeovanis","family":"Gil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna A.","family":"Abbas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1d\u00e1m","family":"Pap","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew S.","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcell","family":"Cserhalmi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilie M.","family":"Legault","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1rmin","family":"S\u0151th","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorina","family":"Jamniczky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Zsoldos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger A.","family":"Barker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gergely","family":"R\u00f3na","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janelle","family":"Drouin-Ouellet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gy\u00f6rgy","family":"Mark\u00f3-Varga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsuzsanna","family":"Darula","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karolina","family":"Pircs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,2]]},"reference":[{"key":"948_CR1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2015.5","volume":"1","author":"GP Bates","year":"2015","unstructured":"Bates GP, Dorsey R, Gusella JF, Hayden MR, Kay C, Leavitt BR, et al. 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Written informed consent was obtained from all human participants prior to the collection of fibroblast samples. Human dermal fibroblasts were obtained from the Huntington\u2019s Disease Clinic at the John van Geest Centre for Brain Repair (Cambridge, UK) and the Fondazione IRCCS Istituto Neurologico Carlo Besta (Milan, Italy) under the following ethical approvals: NHS Research Ethics Committee, United Kingdom (REC 09\/H0311\/88) and Semmelweis University Regional and Institutional Committee of Science and Research Ethics, Hungary (IV-2625-1\/2021\/EKU and IV-1029-1\/2022\/EKU). Experiments involving human fibroblast samples were carried out under the approval IV-2625-1\/2021\/EKU (Semmelweis University Regional and Institutional Committee of Science and Research Ethics, Hungary). Experiments involving human post mortem brain tissue were performed under approval CERC-2025-7229 from the University of Montreal Research Ethics Committee. This study does not involve a clinical trial; therefore: clinical trial registration numbers are not applicable. Human ethics and consent to participate declarations: All required declarations are provided above.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"129"}}