Regulation of tyrosinase trafficking and processing by presenilins: Partial loss of function by familial Alzheimer's disease mutation

Runsheng Wang, Phuong Tang, Pei Wang, Raymond E. Boissy, Hui Zheng

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

Presenilins (PS) are required for γ-secretase cleavage of multiple type I membrane proteins including the amyloid precursor protein and Notch and also have been implicated in regulating intracellular protein trafficking and turnover. Using genetic and pharmacological approaches, we reveal here a unique function of PS in the pigmentation of retinal pigment epithelium and epidermal melanocytes. PS deficiency leads to aberrant accumulation of tyrosinase (Tyr)-containing 50-nm post-Golgi vesicles that are normally destined to melanosomes. This trafficking is γ-secretase-dependent, and abnormal localization of Tyr in the absence of PS is accompanied by the simultaneous accumulation of its C-terminal fragment. Furthermore, we show that the PS1M146V familial Alzheimer's disease mutation exhibits a partial loss-of-function in pigment synthesis. Our results identify Tyr and related proteins as physiological substrates of PS and link γ-secretase activity with intracellular protein transport.

Original languageEnglish (US)
Pages (from-to)353-358
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number2
DOIs
StatePublished - Jan 10 2006
Externally publishedYes

Keywords

  • Knock-in
  • Knock-out
  • Melanocyte
  • Pigmentation
  • γ-secretase

ASJC Scopus subject areas

  • General

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