Protrudin regulates endoplasmic reticulum morphology and function associated with the pathogenesis of hereditary spastic paraplegia

Yutaka Hashimoto, Michiko Shirane, Fumiko Matsuzaki, Shotaro Saita, Takafumi Ohnishi, Keiichi Nakayama

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Protrudin is a membrane protein that regulates polarized vesicular trafficking in neurons. The protrudin gene (ZFYVE27) is mutated in a subset of individuals with hereditary spastic paraplegia (HSP), and protrudin is therefore also referred to as spastic paraplegia (SPG) 33. We have now generated mice that express a transgene for dual epitope-tagged protrudin under control of a neuron-specific promoter, and we have subjected highly purified protrudin-containing complexes isolated from the brain of these mice to proteomics analysis to identify proteins that associate with protrudin. Protrudin was found to interact with other HSP-related proteins including myelin proteolipid protein 1 (SPG2), atlastin-1 (SPG3A), REEP1 (SPG31), REEP5 (similar to REEP1), Kif5A (SPG10), Kif5B, Kif5C, and reticulon 1, 3, and 4 (similar to reticulon 2, SPG12). Membrane topology analysis indicated that one of three hydrophobic segments of protrudin forms a hydrophobic hairpin domain similar to those of other SPG proteins. Protrudin was found to localize predominantly to the tubular endoplasmic reticulum (ER), and forced expression of protrudin promoted the formation and stabilization of the tubularERnetwork. The protrudin(G191V) mutant, which has been identified in a subset of HSP patients, manifested anincreasedintracellularstability,andcellsexpressingthismutant showed an increased susceptibility to ER stress. Our results thus suggest that protrudin contributes to the regulation of ER morphology and function, and that its deregulation by mutation is a causative defect in HSP.

Original languageEnglish
Pages (from-to)12946-12961
Number of pages16
JournalJournal of Biological Chemistry
Volume289
Issue number19
DOIs
Publication statusPublished - Jan 1 2014

Fingerprint

Hereditary Spastic Paraplegia
Endoplasmic Reticulum
Neurons
Paraplegia
Myelin Proteolipid Protein
Proteins
Deregulation
Endoplasmic Reticulum Stress
Epitopes
Brain
Membrane Proteins
Stabilization
Genes
Transgenes
Topology
Proteomics
Membranes
Defects
Mutation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Protrudin regulates endoplasmic reticulum morphology and function associated with the pathogenesis of hereditary spastic paraplegia. / Hashimoto, Yutaka; Shirane, Michiko; Matsuzaki, Fumiko; Saita, Shotaro; Ohnishi, Takafumi; Nakayama, Keiichi.

In: Journal of Biological Chemistry, Vol. 289, No. 19, 01.01.2014, p. 12946-12961.

Research output: Contribution to journalArticle

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