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Expression and Purification of the Human Lipid-sensitive Cation Channel TRPC3 for Structural Determination by Single-particle Cryo-electron Microscopy
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Expression and Purification of the Human Lipid-sensitive Cation Channel TRPC3 for Structural Determination by Single-particle Cryo-electron Microscopy

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

Dongbiao Shen1, Xiang Wang, Xinran Li

  • 1Department of Molecular, Cellular and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University, Ann Arbor 48109, USA.

Nature Communications
|March 15, 2012
PubMed

Insights

Niemann-Pick disease cells show reduced lysosomal calcium release due to lipid buildup blocking the TRPML1 channel. Restoring TRPML1 function corrects cellular defects, offering a therapeutic target for lysosomal storage diseases.

Area of Science:

  • Cell Biology
  • Molecular Medicine
  • Genetics

Background:

  • Lysosomal storage diseases share common features like lipid accumulation, impaired membrane trafficking, and disrupted calcium (Ca2+) homeostasis.
  • The mucolipin transient receptor potential channel 1 (TRPML1) is the primary Ca2+ channel within lysosomes.

Purpose of the Study:

  • To investigate the role of TRPML1 channel function in Niemann-Pick (NP) disease.
  • To explore the impact of sphingomyelin (SM) accumulation on TRPML1 activity.
  • To assess the therapeutic potential of modulating TRPML1 in NP disease.

Main Methods:

  • Utilized a genetically encoded Ca2+ indicator (GCaMP3) attached to TRPML1 to measure lysosomal Ca2+ release.
  • Employed patch-clamp analyses to assess TRPML1 channel activity.
  • Investigated NP-type C cells with varying levels of TRPML1 expression and activity.

Main Results:

  • TRPML1-mediated lysosomal Ca2+ release was significantly reduced in NP disease cells.
  • Accumulated sphingomyelins (SMs) in NP cells inhibited TRPML1 channel activity, while sphingomyelinases (SMases) potentiated it.
  • Enhancing TRPML1 expression or activity in NP-type C cells corrected trafficking defects and reduced lysosomal storage and cholesterol accumulation.

Conclusions:

  • Abnormal lysosomal lipid accumulation, particularly sphingomyelins, impairs TRPML1 channel function.
  • This impairment leads to secondary lysosomal storage by blocking TRPML1- and Ca2+-dependent lysosomal trafficking.
  • Modulating TRPML1 offers a potential therapeutic strategy for Niemann-Pick disease and related lysosomal storage disorders.

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