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

64 Citations (Scopus)

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

Fingerprint

Presenilins
Monophenol Monooxygenase
Alzheimer Disease
Amyloid Precursor Protein Secretases
Mutation
Protein Transport
Melanosomes
Retinal Pigment Epithelium
Amyloid beta-Protein Precursor
Melanocytes
Pigmentation
Membrane Proteins
Pharmacology
Proteins

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Regulation of tyrosinase trafficking and processing by presenilins : Partial loss of function by familial Alzheimer's disease mutation. / Wang, Runsheng; Tang, Phuong; Wang, Pei; Boissy, Raymond E.; Zheng, Hui.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 2, 10.01.2006, p. 353-358.

Research output: Contribution to journalArticle

@article{0d0f6b9896b046f2aa4a7fd5dfc89551,
title = "Regulation of tyrosinase trafficking and processing by presenilins: Partial loss of function by familial Alzheimer's disease mutation",
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.",
keywords = "γ-secretase, Knock-in, Knock-out, Melanocyte, Pigmentation",
author = "Runsheng Wang and Phuong Tang and Pei Wang and Boissy, {Raymond E.} and Hui Zheng",
year = "2006",
month = "1",
day = "10",
doi = "10.1073/pnas.0509822102",
language = "English (US)",
volume = "103",
pages = "353--358",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "2",

}

TY - JOUR

T1 - Regulation of tyrosinase trafficking and processing by presenilins

T2 - Partial loss of function by familial Alzheimer's disease mutation

AU - Wang, Runsheng

AU - Tang, Phuong

AU - Wang, Pei

AU - Boissy, Raymond E.

AU - Zheng, Hui

PY - 2006/1/10

Y1 - 2006/1/10

N2 - 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.

AB - 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.

KW - γ-secretase

KW - Knock-in

KW - Knock-out

KW - Melanocyte

KW - Pigmentation

UR - http://www.scopus.com/inward/record.url?scp=31044438340&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=31044438340&partnerID=8YFLogxK

U2 - 10.1073/pnas.0509822102

DO - 10.1073/pnas.0509822102

M3 - Article

C2 - 16384915

AN - SCOPUS:31044438340

VL - 103

SP - 353

EP - 358

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 2

ER -