Mouse Models of Novel Sphingolipid Biology and Disease Mechanisms

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

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Abstract

This project established three novel mouse models to uncover how sphingolipid metabolism drives neurodegeneration. First, a humanized late-onset Tay-Sachs model carrying the human pathogenic HEXA c.805G>A mutation was generated, reproducing key features of the human disease including GM2 ganglioside storage, neurological decline, and shortened lifespan. Second, a neuron-specific Gba knockout model (Gaucher and Parkinson's disease) was created and crossed with mice expressing the pathogenic human α-synuclein A53T variant, producing a double-mutant with earlier symptom onset, greater glucosylceramide buildup, and elevated phosphorylated α-synuclein; this model revealed the synergy between glucocerebrosidase deficiency and α-synuclein pathology, linking lysosomal dysfunction in Gaucher disease to Parkinson’s disease. Third, a new Sandhoff disease model (Hexb-/-;Tsc2+/-) was used to study the activation of mTOR signaling by reducing Tsc2 genetically. The study revealed that increased mTOR activity improved survival, motor function, dendritic spine density, and synaptic gene expression. The results suggest a new avenue for modifying disease progression.