Lipid storage disorders block lysosomal trafficking by inhibiting a TRP channel and lysosomal calcium release

Dongbiao Shen, Xiang Wang, Xinran Li, Xiaoli Zhang, Zepeng Yao, Shannon Dibble, Xian-ping Dong, Ting Yu, Andrew P. Lieberman, Hollis D. Showalter and Haoxing Xu ()
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Dongbiao Shen: Cellular and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University
Xiang Wang: Cellular and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University
Xinran Li: Cellular and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University
Xiaoli Zhang: Cellular and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University
Zepeng Yao: Cellular and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University
Shannon Dibble: Cellular and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University
Xian-ping Dong: Cellular and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University
Ting Yu: University of Michigan Medical School
Andrew P. Lieberman: University of Michigan Medical School
Hollis D. Showalter: Vahlteich Medicinal Chemistry Core, University of Michigan
Haoxing Xu: Cellular and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University

Nature Communications, 2012, vol. 3, issue 1, 1-11

Abstract: Abstract Lysosomal lipid accumulation, defects in membrane trafficking and altered Ca2+ homoeostasis are common features in many lysosomal storage diseases. Mucolipin transient receptor potential channel 1 (TRPML1) is the principle Ca2+ channel in the lysosome. Here we show that TRPML1-mediated lysosomal Ca2+ release, measured using a genetically encoded Ca2+ indicator (GCaMP3) attached directly to TRPML1 and elicited by a potent membrane-permeable synthetic agonist, is dramatically reduced in Niemann–Pick (NP) disease cells. Sphingomyelins (SMs) are plasma membrane lipids that undergo sphingomyelinase (SMase)-mediated hydrolysis in the lysosomes of normal cells, but accumulate distinctively in lysosomes of NP cells. Patch-clamp analyses revealed that TRPML1 channel activity is inhibited by SMs, but potentiated by SMases. In NP-type C cells, increasing TRPML1's expression or activity was sufficient to correct the trafficking defects and reduce lysosome storage and cholesterol accumulation. We propose that abnormal accumulation of luminal lipids causes secondary lysosome storage by blocking TRPML1- and Ca2+-dependent lysosomal trafficking.

Date: 2012
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DOI: 10.1038/ncomms1735

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