Decreasing ganglioside synthesis delays motor and cognitive symptom onset in Spg11 knockout mice.

Biallelic variants in the SPG11 gene account for the most common form of autosomal recessive hereditary spastic paraplegia characterized by motor and cognitive impairment, with currently no therapeutic option. We previously observed in a Spg11 knockout mouse that neurodegeneration is associated with accumulation of gangliosides in lysosomes. To test whether a substrate reduction therapy could be a therapeutic option, we downregulated the key enzyme involved in ganglioside biosynthesis using an AAV-PHP.

Genetics in hereditary spastic paraplegias: Essential but not enough.

Hereditary spastic paraplegias consist of a group of rare neurodegenerative diseases characterized by lower limb spasticity. These inherited Mendelian disorders show high genetic variability associated with wide clinical diversity. Pathophysiological investigations have suggested that mutations in genes affecting the same cellular pathway generally lead to similar clinical symptoms, highlighting the importance of genetic mutation in these diseases.