Personalized Treatment for Infantile Ascending Hereditary Spastic Paralysis Based on In Silico Strategies

Area of Science:

• Neuroscience
• Genetics
• Drug Discovery

Background:

• Infantile onset hereditary spastic paralysis (IAHSP) is a rare, recessively inherited neurodevelopmental disorder.
• Mutations in the *ALS2* gene, encoding the protein alsin, cause IAHSP by affecting upper motoneuron development.
• Alsin functions as an active tetramer, with dimerization mediated by its C-terminal VPS9 domain.

Purpose of the Study:

• To investigate the pathogenic mechanisms of *ALS2* mutations in IAHSP.
• To identify a therapeutic strategy for IAHSP by targeting alsin's abnormal dimerization.
• To discover a drug candidate capable of restoring functional alsin tetramers.

Main Methods:

• Protein modeling to analyze the R1611W mutation's impact on VPS9 domain stability and flexibility.
• In vitro assays to assess alsin homo-dimerization and tetramer formation.
• Virtual screening to identify compounds that can rescue the mutant alsin phenotype.
• Cellular assays in HeLa cells to validate the drug candidate's efficacy.

Main Results:

• The R1611W mutation disrupts alsin homo-dimerization, preventing the formation of active tetramers.
• Virtual screening identified MK4, a known therapeutic compound, as a potential masker of the R1611W mutation.
• MK4 successfully re-established alsin tetramer formation in HeLa cells harboring the R1611W mutation.

Conclusions:

• The R1611W mutation in the *ALS2* gene impairs alsin function through abnormal dimerization.
• MK4 demonstrates potential as a therapeutic agent for IAHSP by restoring alsin tetramer assembly.
• This study highlights an innovative drug discovery approach for rare neurodevelopmental diseases.