Sphingolipid Biology of Neurodegeneration

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

Linked publications & trials

Abstract

This project on the sphingolipid biology of neurodegeneration has advanced understanding of how lysosomal dysfunction contributes to neuronal decline and has identified therapeutic possibilities in rare and common neurodegenerative diseases. Using late-onset Tay-Sachs (LOTS) disease as a model, we developed an adenine base editing strategy that corrected the major LOTS HEXA mutation, restored β-hexosaminidase A activity, reduced GM2 ganglioside accumulation, delayed neurological symptoms, and extended lifespan in mice. The work demonstrates the feasibility of gene correction for lysosomal storage disorders. We have also demonstrated a synergistic relationship between pathogenic α-synuclein and glucocerebrosidase deficiency, showing that a double-mutant mouse carrying a neuron-specific Gba knockout and the α-synuclein A53T variant exhibited accelerated disease progression, more severe neurodegeneration, and higher levels of glucosylceramide and phosphorylated α-synuclein compared to either defect alone. These findings strengthen the mechanistic link between sphingolipid metabolism and synucleinopathies such as Parkinson’s disease. Finally, work in a Sandhoff disease mouse model revealed that impaired mammalian target of rapamycin (mTOR) signaling is a driver of neurodegeneration, and that genetic reactivation of this pathway improved survival, motor function, dendritic spine density, and synaptic gene expression. Together, these accomplishments highlight how genetic correction, modulation of protein–lipid interactions, and targeting of downstream signaling pathways can converge to inform therapeutic strategies, illustrating the broad impact of sphingolipid biology on both rare inherited disorders and more prevalent neurodegenerative diseases.