Abstract
Mutations of the SPAST gene that encodes the microtubule-severing enzyme called spastin are the chief cause of Hereditary Spastic Paraplegia. Growing evidence indicates that pathogenic mutations functionally compromise the spastin protein and endow it with toxic gain-of-function properties. With each of these two factors potentially relevant to disease etiology, the present article discusses possible therapeutic strategies that may ameliorate symptoms in patients suffering from SPAST-based Hereditary Spastic Paraplegia, which is usually termed SPG4-HSP.
Highlights
Mutations of the SPAST gene account for the plurality of cases of autosomal dominant Hereditary Spastic Paraplegia (HSP), a heritable neurodegenerative disease involving progressive weakness and spasticity of lower limbs [1]
An early idea was that insufficient levels of functional spastin account for the degeneration of the corticospinal axons [5,6,7,8,9,10,11,12], but more recent studies suggest that the gain-of-function toxicity of the mutant spastin is the primary culprit [13,14,15]
We have reported experimental data suggesting that while the gain-of-function component drives the SPG4-HSP phenotype, the loss-of-function component exacerbates the gain-of-function component [3,15]
Summary
Mutations of the SPAST gene ( called SPG4) account for the plurality of cases of autosomal dominant Hereditary Spastic Paraplegia (HSP), a heritable neurodegenerative disease involving progressive weakness and spasticity of lower limbs [1]. SPG4-HSP is usually but not always adult-onset, with symptoms mainly resulting from degeneration of the corticospinal tracts. An early idea was that insufficient levels of functional spastin account for the degeneration of the corticospinal axons [5,6,7,8,9,10,11,12], but more recent studies suggest that the gain-of-function toxicity of the mutant spastin is the primary culprit [13,14,15]. We have posited that both contribute, with loss of spastin function rendering axons more vulnerable to the toxic effects of the mutant protein [15].
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