Peripheral immune system modulates Purkinje cell degeneration in Niemann–Pick disease type C1

Author:

Yasuda Toru1ORCID,Uchiyama Toru1,Watanabe Nobuyuki1,Ito Noriko2ORCID,Nakabayashi Kazuhiko2,Mochizuki Hideki3,Onodera Masafumi1

Affiliation:

1. Department of Human Genetics, National Center for Child Health and Development

2. Department of Maternal-Fetal Biology, National Center for Child Health and Development

3. Department of Neurology, Graduate School of Medicine, Osaka University, Osaka, Japan

Abstract

Niemann–Pick disease type C1 (NPC1) is a fatal lysosomal storage disorder characterized by progressive neuronal degeneration. Its key pathogenic events remain largely unknown. We have, herein, found that neonatal BM–derived cell transplantation can ameliorate Purkinje cell degeneration in NPC1 mice. We subsequently addressed the impact of the peripheral immune system on the neuropathogenesis observed in NPC1 mice. The depletion of mature lymphocytes promoted NPC1 phenotypes, thereby suggesting a neuroprotective effect of lymphocytes. Moreover, the peripheral infusion of CD4-positive cells (specifically, of regulatory T cells) from normal healthy donor ameliorated the cerebellar ataxic phenotype and enhanced the survival of Purkinje cells. Conversely, the depletion of regulatory T cells enhanced the onset of the neurological phenotype. On the other hand, circulating inflammatory monocytes were found to be involved in the progression of Purkinje cell degeneration, whereas the depletion of resident microglia had little effect. Our findings reveal a novel role of the adaptive and the innate immune systems in NPC1 neuropathology.

Funder

JSPS KAKENHI

Publisher

Life Science Alliance, LLC

Subject

Health, Toxicology and Mutagenesis,Plant Science,Biochemistry, Genetics and Molecular Biology (miscellaneous),Ecology

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