NIH R01 · 2024
Mechanisms of Mutant Prion Protein Aggregation Within Endolysosomal Pathways
Ultrastructural studies of human patient brains with prion disease have revealed the accumulation of misfolded PrP within dystrophic neurites inside endolysosomes. Other complex structures co- exist within these dystrophies and are now considered common features of prion pathologies, including autophagic vacuole-like membrane-bound organelles, lysosomal electron-dense bodies, and enlarged endolysosomes. The mechanisms leading to the formation of these structures remain unknown. Our studies have identified an endolysosomal pathway in mammalian neurons that we call axonal rapid endosomal sorting and transport-dependent aggregation (ARESTA), that drives the formation of neurotoxic axonal…
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