Regulation of Tyrosinase Trafficking and Processing by Presenilins: Partial Loss of Function by Familial Alzheimer's Disease Mutation

• Published in: Proceedings of the National Academy of Sciences - PNAS 2006-01, Vol.103 (2), p.353-358
• Main Authors: Wang, Runsheng, Tang, Phuong, Wang, Pei, Boissy, Raymond E., Zheng, Hui
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - embryology; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Alzheimers disease; Animals; Biological Sciences; Cellular biology; Embryo, Mammalian - embryology; Embryo, Mammalian - metabolism; Enzymes; Epithelium - embryology; Epithelium - metabolism; Gene expression regulation; Genetic mutation; Golgi Apparatus - metabolism; Melanin; Melanins - biosynthesis; Melanocytes; Melanocytes - metabolism; Melanocytes - ultrastructure; Melanosomes; Membrane Proteins - deficiency; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Electron, Transmission; Molecules; Monophenol Monooxygenase - genetics; Monophenol Monooxygenase - metabolism; Mutation; Mutation - genetics; Pigmentation; Pigments; Presenilin-1; Presenilin-2; Protein Transport; Proteins; Retina; Retina - embryology; Retina - metabolism; Skin - embryology; Skin - metabolism; Tyrosine - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0509822102

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.