SPAST, encoding the microtubule-severing enzyme spastin, is a crucial gene [1,2,6]. Microtubule severing is an essential process in cells, influencing various cellular functions such as cell division, intracellular transport, and axonal growth and maintenance [1,2,6]. Mutations in SPAST are the chief cause of Hereditary Spastic Paraplegia (HSP), specifically SPG4-HSP, highlighting its significance in maintaining neural function [1,2,4,5,6,7]. Genetic models, like mouse models, are valuable for studying SPAST's function.

There is controversy regarding the etiology of SPAST-based HSP. Some suggest haploinsufficiency, while others propose toxic gain-of-function properties of mutant spastin proteins [2]. A new hypothesis posits that haploinsufficiency may not directly cause the disease but makes the corticospinal tracts vulnerable to a second hit, often the mutant spastin proteins [2]. Studies on patients with SPAST microrearrangements indicate that nonsense-mediated decay degradation is not the only mechanism of hereditary spastic paraplegia in such cases [3]. Also, different mutations in SPAST, like the p.Arg499His mutation, are associated with infantile-onset complicated spastic paraplegia, expanding the understanding of genotype-phenotype correlations [4].

In conclusion, SPAST is essential for microtubule severing, which is crucial for normal cellular and neural function. Mouse models and studies on patients with SPAST mutations have provided insights into the etiology of HSP, especially SPG4-HSP. Understanding SPAST's function through these models helps in developing therapeutic strategies for this form of hereditary spastic paraplegia [1,2,4].

References:

1. Mohan, Neha, Qiang, Liang, Morfini, Gerardo, Baas, Peter W. 2021. Therapeutic Strategies for Mutant SPAST-Based Hereditary Spastic Paraplegia. In Brain sciences, 11, . doi:10.3390/brainsci11081081. https://pubmed.ncbi.nlm.nih.gov/34439700/

2. Qiang, Liang, Piermarini, Emanuela, Baas, Peter W. 2019. New hypothesis for the etiology of SPAST-based hereditary spastic paraplegia. In Cytoskeleton (Hoboken, N.J.), 76, 289-297. doi:10.1002/cm.21528. https://pubmed.ncbi.nlm.nih.gov/31108029/

3. Elert-Dobkowska, Ewelina, Stepniak, Iwona, Radziwonik-Fraczyk, Wiktoria, Beetz, Christian, Sulek, Anna. 2024. SPAST Intragenic CNVs Lead to Hereditary Spastic Paraplegia via a Haploinsufficiency Mechanism. In International journal of molecular sciences, 25, . doi:10.3390/ijms25095008. https://pubmed.ncbi.nlm.nih.gov/38732227/

4. Nan, Haitian, Shiraku, Hiroshi, Mizuno, Tomoko, Takiyama, Yoshihisa. 2021. A p.Arg499His mutation in SPAST is associated with infantile-onset complicated spastic paraplegia: a case report and review of the literature. In BMC neurology, 21, 439. doi:10.1186/s12883-021-02478-0. https://pubmed.ncbi.nlm.nih.gov/34753439/

5. Høyer, Helle, Nakken, Ola, Holmøy, Trygve. 2023. A Novel SPAST Variant Associated with Isolated Spastic Paraplegia. In Case reports in genetics, 2023, 4553365. doi:10.1155/2023/4553365. https://pubmed.ncbi.nlm.nih.gov/38186854/

6. Verriello, Lorenzo, Lonigro, Incoronata Renata, Pessa, Maria Elena, Gigli, Gian Luigi, Curcio, Francesco. 2021. Amplifying the spectrum of SPAST gene mutations. In Acta bio-medica : Atenei Parmensis, 92, e2021220. doi:10.23750/abm.v92iS1.11608. https://pubmed.ncbi.nlm.nih.gov/35132972/

7. Méreaux, Jean-Loup, Banneau, Guillaume, Papin, Mélanie, Leguern, Eric, Stevanin, Giovanni. . Clinical and genetic spectra of 1550 index patients with hereditary spastic paraplegia. In Brain : a journal of neurology, 145, 1029-1037. doi:10.1093/brain/awab386. https://pubmed.ncbi.nlm.nih.gov/34983064/