title: Lipid storage disorders block lysosomal trafficking by inhibiting a TRP channel and lysosomal calcium release.
abstract: Lysosomal lipid accumulation, defects in membrane trafficking and altered Ca(2+) homoeostasis are common features in many lysosomal storage diseases. Mucolipin transient receptor potential channel 1 (TRPML1) is the principle Ca(2+) channel in the lysosome. Here we show that TRPML1-mediated lysosomal Ca(2+) release, measured using a genetically encoded Ca(2+) 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 Ca(2+)-dependent lysosomal trafficking.
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University, Ann Arbor 48109, USA.
authors.forename: Dongbiao
authors.initials: D
authors.lastname: Shen
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.forename: Xinran
authors.initials: X
authors.lastname: Li
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.forename: Zepeng
authors.initials: Z
authors.lastname: Yao
authors.forename: Shannon
authors.initials: S
authors.lastname: Dibble
authors.forename: Xian-ping
authors.initials: XP
authors.lastname: Dong
authors.forename: Ting
authors.initials: T
authors.lastname: Yu
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Lieberman
authors.forename: Hollis D
authors.initials: HD
authors.lastname: Showalter
authors.forename: Haoxing
authors.initials: H
authors.lastname: Xu
mesh_terms: D000818:Animals; D019556:COS Cells; D002118:Calcium / Q000378:metabolism*; D002522:Chlorocebus aethiops; D002784:Cholesterol / Q000378:metabolism; D006224:Cricetinae; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009542:Niemann-Pick Diseases / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010797:Phthalimides / Q000494:pharmacology; D021381:Protein Transport; D011804:Quinolines / Q000494:pharmacology; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013109:Sphingomyelins / Q000378:metabolism; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050051:Transient Receptor Potential Channels / Q000378:metabolism*
chemical_list: C416674:MCOLN1 protein, human; C000599935:ML-SA1 compound; D010797:Phthalimides; D011804:Quinolines; D013109:Sphingomyelins; D050052:TRPC Cation Channels; D050051:Transient Receptor Potential Channels; D002784:Cholesterol; D013108:Sphingomyelin Phosphodiesterase; D002118:Calcium