Personalized Treatment for Infantile Ascending Hereditary Spastic Paralysis Based on In Silico Strategies
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 <i>ALS2</i> gene, encoding for the protein alsin and involved in differentiati...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-10-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/27/20/7063 |
| _version_ | 1797470849475805184 |
|---|---|
| author | Matteo Rossi Sebastiano Giuseppe Ermondi Kai Sato Asako Otomo Shinji Hadano Giulia Caron |
| author_facet | Matteo Rossi Sebastiano Giuseppe Ermondi Kai Sato Asako Otomo Shinji Hadano Giulia Caron |
| author_sort | Matteo Rossi Sebastiano |
| collection | DOAJ |
| description | 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 <i>ALS2</i> 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 <i>ALS2</i> 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’s 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. |
| first_indexed | 2024-03-09T19:41:45Z |
| format | Article |
| id | doaj.art-c25b83e04e4043e699a1414a94ff4c8d |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T19:41:45Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-c25b83e04e4043e699a1414a94ff4c8d2023-11-24T01:36:43ZengMDPI AGMolecules1420-30492022-10-012720706310.3390/molecules27207063Personalized Treatment for Infantile Ascending Hereditary Spastic Paralysis Based on In Silico StrategiesMatteo Rossi Sebastiano0Giuseppe Ermondi1Kai Sato2Asako Otomo3Shinji Hadano4Giulia Caron5Molecular Biotechnology and Health Sciences Department, University of Torino, Quarello 15, 10135 Torino, ItalyMolecular Biotechnology and Health Sciences Department, University of Torino, Quarello 15, 10135 Torino, ItalyMolecular Neuropathobiology Laboratory, Department of Molecular Life Sciences, Tokai University School of Medicine, 143 Shimokasuya, Isehara 259-1193, JapanMolecular Neuropathobiology Laboratory, Department of Molecular Life Sciences, Tokai University School of Medicine, 143 Shimokasuya, Isehara 259-1193, JapanMolecular Neuropathobiology Laboratory, Department of Molecular Life Sciences, Tokai University School of Medicine, 143 Shimokasuya, Isehara 259-1193, JapanMolecular Biotechnology and Health Sciences Department, University of Torino, Quarello 15, 10135 Torino, ItalyInfantile 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 <i>ALS2</i> 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 <i>ALS2</i> 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’s 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.https://www.mdpi.com/1420-3049/27/20/7063infantile onset ascending hereditary spastic paralysisALS2virtual screeningvitamin Kdrug repurposingpersonalized medicine |
| spellingShingle | Matteo Rossi Sebastiano Giuseppe Ermondi Kai Sato Asako Otomo Shinji Hadano Giulia Caron Personalized Treatment for Infantile Ascending Hereditary Spastic Paralysis Based on In Silico Strategies Molecules infantile onset ascending hereditary spastic paralysis ALS2 virtual screening vitamin K drug repurposing personalized medicine |
| title | Personalized Treatment for Infantile Ascending Hereditary Spastic Paralysis Based on In Silico Strategies |
| title_full | Personalized Treatment for Infantile Ascending Hereditary Spastic Paralysis Based on In Silico Strategies |
| title_fullStr | Personalized Treatment for Infantile Ascending Hereditary Spastic Paralysis Based on In Silico Strategies |
| title_full_unstemmed | Personalized Treatment for Infantile Ascending Hereditary Spastic Paralysis Based on In Silico Strategies |
| title_short | Personalized Treatment for Infantile Ascending Hereditary Spastic Paralysis Based on In Silico Strategies |
| title_sort | personalized treatment for infantile ascending hereditary spastic paralysis based on in silico strategies |
| topic | infantile onset ascending hereditary spastic paralysis ALS2 virtual screening vitamin K drug repurposing personalized medicine |
| url | https://www.mdpi.com/1420-3049/27/20/7063 |
| work_keys_str_mv | AT matteorossisebastiano personalizedtreatmentforinfantileascendinghereditaryspasticparalysisbasedoninsilicostrategies AT giuseppeermondi personalizedtreatmentforinfantileascendinghereditaryspasticparalysisbasedoninsilicostrategies AT kaisato personalizedtreatmentforinfantileascendinghereditaryspasticparalysisbasedoninsilicostrategies AT asakootomo personalizedtreatmentforinfantileascendinghereditaryspasticparalysisbasedoninsilicostrategies AT shinjihadano personalizedtreatmentforinfantileascendinghereditaryspasticparalysisbasedoninsilicostrategies AT giuliacaron personalizedtreatmentforinfantileascendinghereditaryspasticparalysisbasedoninsilicostrategies |