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Neuronal cell death caused by inhibition of intracellular cholesterol trafficking is caspase-dependent and associated with activation of mitochondrial apoptosis pathway

journal contribution
posted on 2023-05-17, 01:42 authored by Huang, Z, Hou, Q, Cheung, NS, Li, QT
An elevated level of cholesterol in mitochondrial membranes of Niemann-Pick disease type C1 (NPC1) mouse brains and neural cells has been found to cause mitochondrial dysfunction. In this study, we demonstrate that inhibition of intracellular cholesterol trafficking in primary neurons by class 2 amphiphiles, which mimics the major biochemical and cellular feature of NPC1, led to not only impaired mitochondrial function but also activation of the mitochondrial apoptosis pathway. In activation of this pathway both cytochrome c and Smac/Diablo were released but apoptosis-inducing factor (AIF) was not involved. Treatment of the neurons with taurine, a caspase 9-specific inhibitor, could prevent the amphiphile-induced apoptotic cell death, suggesting that formation of apoptosome, followed by caspase 9 and caspase 3 activation, might play a critical role in the neuronal death pathway. Taken together, the mitochondria-dependent death cascade induced by blocking intracellular cholesterol trafficking was caspase dependent. The findings provide clues for both understanding the molecular basis of neurodegeneration in NPC1 disease and developing therapeutic strategies for treatment of this disorder.

History

Publication title

Journal of Neurochemistry

Volume

97

Pagination

280-291

ISSN

0022-3042

Department/School

Menzies Institute for Medical Research

Publisher

Blackwell Publishing Ltd

Place of publication

9600 Garsington Rd, Oxford, England, Oxon, Ox4 2Dg

Repository Status

  • Restricted

Socio-economic Objectives

Clinical health not elsewhere classified

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