Defining the subcellular biology of brain aging and neurodegeneration (renewed)
This team plans to map how age-related dysfunction of cellular waste disposal in lysosomes could lead to neurodegenerative diseases, potentially laying the foundation for a map of organelle function in the brain. This is an extension from a Catalyst Grant Award.
Research Summary
Mapping Cell-Type-Specific Lysosomal Content
In our recent manuscript (Ghoochani et al, Biorxiv, 2024, under favorable revision in Cell), we developed a high-resolution lysosomal protein atlas from neurons, astrocytes, microglia, and oligodendrocytes. This comprehensive resource revealed the diverse and cell-type-specific lysosomal composition across brain regions. Notably, we identified dozens of previously uncharacterized lysosomal proteins, broadening our understanding of lysosomal compositions and functions. A key finding was the identification of SLC45A1 as a neuron-specific lysosomal protein whose mutations causes a neurological disease that we redefined as lysosomal storage disorder (LSD) through our work. Mechanistic studies demonstrated its dual role in V-ATPase stabilization and sugar transport, critical for lysosomal pH regulation and neuronal health. This discovery advances the understanding of lysosomal contributions to brain resilience and protection against neurodegeneration. As part of the second phase of this grant, we are performing similar studies on lysosomes from aged animals. Together with the Knight Initiative, we are developing public-facing internet resources to access all our experimental data to broaden the impact of our work.
