Spast-flox Mouse

Spast, encoded by the SPAST gene, is a microtubule-severing enzyme, being a member of the ATPases Associated with a variety of cellular Activity (AAA) family [1,9]. Its normal function is crucial for the proper maintenance and function of microtubules, which are involved in numerous cellular processes such as intracellular transport, cell division, and axonal elongation. Mutations in the SPAST gene are the chief cause of Hereditary Spastic Paraplegia (HSP), particularly SPG4-HSP [1].

There is controversy regarding the disease etiology. One view is that haploinsufficiency does not directly cause the disease but makes the corticospinal tracts vulnerable to a "second hit", often the mutant spastin proteins [2]. Intragenic copy-number variations (CNVs) in SPAST can lead to HSP via a haploinsufficiency mechanism [4]. Different mutations in SPAST, like an AluYb9 insertion in intron 16 causing splicing alteration [3], or a p.Arg499His mutation associated with infantile-onset complicated spastic paraplegia [5], contribute to the disease phenotype. Also, a novel c.1751A > G p.(Asp584Gly) variant in SPAST was found in an isolated case of SPG4 [6], and a new intragenic microdeletion in exon 13 was likely pathogenic [9]. Patient-derived stem cells and non-neuronal cells (PBMCs) from HSP-SPAST patients have shown reduced levels of acetylated α-tubulin, a form of stabilized microtubules [7,8].

In conclusion, Spast is essential for microtubule-related cellular functions. Studies, including those on gene mutations and using patient-derived cells, have revealed its significant role in the pathogenesis of Hereditary Spastic Paraplegia. Understanding Spast's function and the effects of its mutations helps in developing potential therapeutic strategies for HSP patients [1].