LC3 Immunostaining in the Inferior Olivary Nuclei of Cats With Niemann-Pick Disease Type C1 Is Associated With Patterned Purkinje Cell Loss

Brittney L Gurda; Jessica H Bagel; Samantha J Fisher; Mark L Schultz; Andrew P Lieberman; Peter Hand; Charles H Vite; Gary P Swain

doi:10.1093/jnen/nlx119

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LC3 Immunostaining in the Inferior Olivary Nuclei of Cats With Niemann-Pick Disease Type C1 Is Associated With Patterned Purkinje Cell Loss

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LC3 Immunostaining in the Inferior Olivary Nuclei of Cats With Niemann-Pick Disease Type C1 Is Associated With Patterned Purkinje Cell Loss

Brittney L Gurda, Jessica H Bagel, Samantha J Fisher, Mark L Schultz, Andrew P Lieberman, Peter Hand, Charles H Vite and Gary P Swain

Journal of neuropathology and experimental neurology, Vol.77(3), pp.229-245

03/01/2018

DOI: 10.1093/jnen/nlx119

PMCID: PMC5989620

PMID: 29346563

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Abstract

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 (HPβCD) ameliorated neurological dysfunction, reduced cholesterol and sphingolipid accumulation, and increased lifespan in NPC1 cats. LC3 pathology was reduced in treated animals suggesting that HPβCD 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 HPβCD.

2-Hydroxypropyl-beta-cyclodextrin - therapeutic use

Animals

Calbindins - metabolism

Cats - genetics

Disease Models, Animal

Microtubule-Associated Proteins - metabolism

Mutation - genetics

Niemann-Pick C1 Protein - genetics

Niemann-Pick Disease, Type C - drug therapy

Niemann-Pick Disease, Type C - genetics

Niemann-Pick Disease, Type C - pathology

Niemann-Pick Disease, Type C - veterinary

Olivary Nucleus - metabolism

Olivary Nucleus - pathology

Purkinje Cells - pathology

Details

Title: Subtitle: LC3 Immunostaining in the Inferior Olivary Nuclei of Cats With Niemann-Pick Disease Type C1 Is Associated With Patterned Purkinje Cell Loss
Creators: Brittney L Gurda - University of Pennsylvania
Jessica H Bagel - University of Pennsylvania
Samantha J Fisher - University of Pennsylvania
Mark L Schultz - University of Michigan Medical School
Andrew P Lieberman - University of Michigan
Peter Hand - University of Pennsylvania
Charles H Vite - University of Pennsylvania
Gary P Swain - University of Pennsylvania
Resource Type: Journal article
Publication Details: Journal of neuropathology and experimental neurology, Vol.77(3), pp.229-245
DOI: 10.1093/jnen/nlx119
PMID: 29346563
PMCID: PMC5989620
NLM abbreviation: J Neuropathol Exp Neurol
ISSN: 0022-3069
eISSN: 1554-6578
Grant note: T32 NS007222 / NINDS NIH HHS R01 NS063967 / NINDS NIH HHS R01 NS096087 / NINDS NIH HHS T32 NS007413 / NINDS NIH HHS P40 OD010939 / NIH HHS
Language: English
Date published: 03/01/2018
Academic Unit: Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics
Record Identifier: 9984366289902771

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