{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T12:57:16Z","timestamp":1791896236141,"version":"4.3.4"},"reference-count":50,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T00:00:00Z","timestamp":1666137600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CRT Foundation (Progam \u201cErogazioni Ordinarie\u201d 2019)","award":["BMSS.2022.06\/XXIV"],"award-info":[{"award-number":["BMSS.2022.06\/XXIV"]}]},{"name":"CRT Foundation (Progam \u201cErogazioni Ordinarie\u201d 2019)","award":["19H03551"],"award-info":[{"award-number":["19H03551"]}]},{"name":"Italian Ministry of University and Research","award":["BMSS.2022.06\/XXIV"],"award-info":[{"award-number":["BMSS.2022.06\/XXIV"]}]},{"name":"Italian Ministry of University and Research","award":["19H03551"],"award-info":[{"award-number":["19H03551"]}]},{"name":"Japanese Society for the Promotion of Science","award":["BMSS.2022.06\/XXIV"],"award-info":[{"award-number":["BMSS.2022.06\/XXIV"]}]},{"name":"Japanese Society for the Promotion of Science","award":["19H03551"],"award-info":[{"award-number":["19H03551"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Infantile onset hereditary spastic paralysis (IAHSP) is a rare neurological disease diagnosed in less than 50 children worldwide. It is transmitted with a recessive pattern and originates from mutations of the ALS2 gene, encoding for the protein alsin and involved in differentiation and maintenance of the upper motoneuron. The exact pathogenic mechanisms of IAHSP and other neurodevelopmental diseases are still largely unknown. However, previous studies revealed that, in the cytosolic compartment, alsin is present as an active tetramer, first assembled from dimer pairs. The C-terminal VPS9 domain is a key interaction site for alsin dimerization. Here, we present an innovative drug discovery strategy, which identified a drug candidate to potentially treat a patient harboring two ALS2 mutations: one truncation at lysine 1457 (not considered) and the substitution of arginine 1611 with a tryptophan (R1611W) in the C-terminus VPS9. With a protein modeling approach, we obtained a R1611W mutant model and characterized the impact of the mutation on the stability and flexibility of VPS9. Furthermore, we showed how arginine 1611 is essential for alsin\u2019s homo-dimerization and how, when mutated to tryptophan, it leads to an abnormal dimerization pattern, disrupting the formation of active tetramers. Finally, we performed a virtual screening, individuating an already therapy-approved compound (MK4) able to mask the mutant residue and re-establishing the alsin tetramers in HeLa cells. MK4 has now been approved for compassionate use.<\/jats:p>","DOI":"10.3390\/molecules27207063","type":"journal-article","created":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T22:19:53Z","timestamp":1666217993000},"page":"7063","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Personalized Treatment for Infantile Ascending Hereditary Spastic Paralysis Based on In Silico Strategies"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9925-1904","authenticated-orcid":false,"given":"Matteo","family":"Rossi Sebastiano","sequence":"first","affiliation":[{"name":"Molecular Biotechnology and Health Sciences Department, University of Torino, Quarello 15, 10135 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Ermondi","sequence":"additional","affiliation":[{"name":"Molecular Biotechnology and Health Sciences Department, University of Torino, Quarello 15, 10135 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Sato","sequence":"additional","affiliation":[{"name":"Molecular Neuropathobiology Laboratory, Department of Molecular Life Sciences, Tokai University School of Medicine, 143 Shimokasuya, Isehara 259-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asako","family":"Otomo","sequence":"additional","affiliation":[{"name":"Molecular Neuropathobiology Laboratory, Department of Molecular Life Sciences, Tokai University School of Medicine, 143 Shimokasuya, Isehara 259-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4997-3968","authenticated-orcid":false,"given":"Shinji","family":"Hadano","sequence":"additional","affiliation":[{"name":"Molecular Neuropathobiology Laboratory, Department of Molecular Life Sciences, Tokai University School of Medicine, 143 Shimokasuya, Isehara 259-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Caron","sequence":"additional","affiliation":[{"name":"Molecular Biotechnology and Health Sciences Department, University of Torino, Quarello 15, 10135 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1086\/342359","article-title":"Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene","volume":"71","author":"Lesca","year":"2002","journal-title":"Am. 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