A pathogenic alpha synuclein variant exacerbates 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 α-synuclein (α-syn), in which reduced GBA levels lead to elevated α-syn. To further explore this connection specifically within neurons in vivo, we have introduced a human pathogenic variant of α-syn, A53T, into a neuron-specific Gba-KO mouse. This double variant mouse exhibited a reduced lifespan and more pronounced weight loss relative to the neuron-specific Gba-KO mouse, demonstrating a faster disease course and more severe phenotype. Additionally, their brains showed elevated levels of glucosylceramide and phosphorylated α-syn, while glucosylsphingosine levels were unchanged. Pathogenic α-syn had a greater effect on lifespan when combined with the neuron-specific Gba-KO than with KOs in Hexa or Hexb, genes linked to Tay-Sachs and Sandhoff disease, respectively. This model reveals that pathogenic α-syn amplifies GBA-related disease mechanisms within neurons, leading to an earlier and more severe disease course than with deficiencies in other glycosphingolipid-degrading enzymes.