A collaborative study “Modeling gain-of-function and loss-of-function components of SPAST-based hereditary spastic paraplegia using transgenic mice” contributed by Prof. Dr. Arzu Karabay and R.A. Şeyma Akarsu from ITU Molecular Biology and Genetics Department (MBG) was published in the journal “Human Molecular Genetics”.


Hereditary spastic paraplegia (HSP) is a rare neurodegenerative disease that affects the lower extremities through degeneration in the corticospinal tract accompanied by axonal swelling. Spastic Paraplegia 4 (HSP-SPG4), the most common type of HSP, is caused by mutations in the SPAST (SPG4) gene encoding Spastin protein, a type of microtubule-severing protein. One of the major obstacles to the development of effective therapies for this disease is the lack of a vertebrate model that recapitulates the same etiology and symptoms of HSP-SPG4. hSPAST-C448Y mice, which express human mutant spastin at the ROSA26 locus, display corticospinal dieback and gait deficiencies but not axonal swellings. While axonal swelling is observed in mouse spastin gene (Spast)-knockout (KO) mice but not corticospinal dieback or gait deficiencies. To explore the hypothesis that the reduction of spastin function leading to axonal swelling is not the cause of the disease but may increase the toxic effects of the mutant protein, the offspring obtained by crossing Spast-KO and hSPAST-C448Y were compared histologically and behaviorally with their parent lines. The crossbred animals exhibited axonal swellings as well as earlier onset, worsened gait deficiencies and corticospinal dieback compared to hSPAST-C448Y mouse. Considering the changes in histone deacetylases 6 activity and modifications of tubulin in the axon, all these results were concluded that all three transgenic mouse lines obtained in the study would be useful in investigating a different pathology of the disease pathology. In addition, the crossbred mice obtained in the study are the best vertebrate model for testing potential treatments for HSP-SPG4.