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.
Keywords: HDAC6; Hereditary Spastic Paraplegia; SPAST; SPG4-HSP; autophagy; casein kinase 2; gain-of-function; gene therapy; haploinsufficiency; loss-of-function; microtubule; spastin.