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PMID: 16384915 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 103 ·No. 2 ·2006-01-10 ·Pages 353-8

Wang R, Tang P, Wang P, Boissy RE, Zheng H

Abstract

Presenilins (PS) are required for gamma-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 gamma-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 gamma-secretase activity with intracellular protein transport.

MeSH Terms
Alzheimer Disease/embryology,genetics,metabolism,pathology Animals Embryo, Mammalian/embryology,metabolism Epithelium/embryology,metabolism Golgi Apparatus/metabolism Melanins/biosynthesis Melanocytes/metabolism,ultrastructure Membrane Proteins/deficiency,genetics,metabolism Mice Mice, Inbred C57BL Mice, Knockout Microscopy, Electron, Transmission Monophenol Monooxygenase/genetics,metabolism Mutation/genetics Pigmentation Presenilin-1 Presenilin-2 Protein Transport Retina/embryology,metabolism Skin/embryology,metabolism Tyrosine/metabolism
Chemicals
Melanins Membrane Proteins Presenilin-1 Presenilin-2 Tyrosine Monophenol Monooxygenase
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Wang Runsheng
Huffington Center on Aging and Departments of Molecular and Human Genetics and Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Tang Phuong
Wang Pei
Boissy Raymond E
Zheng Hui
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0509822102
Published
2006-01-10
Epub
2005-00-29
Pages
353-8
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC1326180
Subset
IM
Grants
NIA NIH HHS · T32 AG000183 · United States
NINDS NIH HHS · R01 NS040039 · United States
NINDS NIH HHS · NS40039 · United States
NIAMS NIH HHS · AR45429 · United States
NIA NIH HHS · R01 AG020670 · United States
NIAMS NIH HHS · R01 AR045429 · United States
NIA NIH HHS · AG20670 · United States
External Links
PubMed source DOI: 10.1073/pnas.0509822102 PMC Full Text View journal details
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