A pathogenic alpha synuclein variant exacerabtes disease progression in a neuron-specific Gba KO mouse

GBA variants are among the most significant genetic risk factors for synucleinopathies including Parkinson’s disease and dementia with Lewy bodies. The GBA gene encodes the lysosomal enzyme glucocerebrosidase (GBA), which is essential for glycosphingolipid catabolism. There is a reciprocal relationship between GBA and -synuclein ( -syn), in which reduced GBA levels lead to elevated -syn. To explore this relationship specifically within neurons in vivo, we have introduced a human pathogenic variant of -syn, A53T, into a neuron-specific Gba-KO mouse. This double variant mouse exhibited a reduced lifespan relative to the neuron-specific Gba-KO mouse and more pronounced weight loss, demonstrating a faster disease course and more severe phenotype than neuron-specific Gba-KO mice. Additionally, their brains showed elevated levels of glucosylceramide (GlcCer) and phosphorylated -syn compared to the single-variant mice. Surprisingly, glucosylsphingosine (GlcSph) levels were comparable between double-variant and neuron-specific Gba-KO mice, suggesting impaired GlcSph generation. A small number of genes were significantly different between double variant and neuron-specific Gba-KO mice. These findings suggest that GlcCer accumulation, due to GBA loss, interacts with -syn in neurons, driving increased pathogenic -syn levels and modulating GlcCer metabolism.