Journal
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
Volume 77, Issue 3, Pages 229-245Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/jnen/nlx119
Keywords
Autophagy; Axonal degeneration; Cerebellar degeneration; LC3; Lysosomal storage disease; Neurodegeneration; Neuronal pathway
Categories
Funding
- Ara Parseghian Medical Research Foundation
- Dana's Angels Research Trust
- Race for Adam
- National Niemann Pick Disease Foundation
- Support of Accelerated Research for Niemann Pick Type C disease (SOAR-NPC)
- [NIH-R01-NS-096087]
- [R01-NS-063967]
- [P40-OD-010939]
- [T32-NS-007222]
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The feline model of Niemann-Pick disease, type C1 (NPC1) recapitulates the clinical, neuropathological, and biochemical abnormalities present in children with NPC1. The hallmarks of disease are the lysosomal storage of unesterified cholesterol and multiple sphingolipids in neurons, and the spatial and temporal distribution of Purkinje cell death. In feline NPC1 brain, microtubule-associated protein 1 light chain 3 (LC3) accumulations, indicating autophagosomes, were found within axons and presynaptic terminals. High densities of accumulated LC3 were seen in subdivisions of the inferior olive, which project to cerebellar regions that show the most Purkinje cell loss, suggesting that autophagic abnormalities in specific climbing fibers may contribute to the spatial pattern of Purkinje cell loss seen. Biweekly intrathecal administration of 2-hydroxypropyl-beta cyclodextrin (HP beta CD) ameliorated neurological dysfunction, reduced cholesterol and sphingolipid accumulation, and increased lifespan in NPC1 cats. LC3 pathology was reduced in treated animals suggesting that HP beta CD administration also ameliorates autophagic abnormalities. This study is the first to (i) identify specific brain regions exhibiting autophagic abnormalities in any species with NPC1, (ii) provide evidence of differential vulnerability among discrete brain nuclei and pathways, and (iii) show the amelioration of these abnormalities in NPC1 cats treated with HP beta CD.
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