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

Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 02/2006; 103(2):353-8. DOI: 10.1073/pnas.0509822102
Source: PubMed


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.

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    • "BACE1-digested APP CTFs are subsequently cleaved by the γ-secretase complex to release Aβ. In addition, γ-secretase cleaves a series of functionally important substrates such as NOTCH [138] and tyrosinase [139]. γ-secretase activity is produced from a high molecular weight complex consisting of at least four transmembrane components: presenilin (PS, with two mammalian homologs as PS1 and PS2), nicastrin, anterior pharynx-defective-1 (APH-1), and presenilin enhancer-2 (PEN2) [140,141]. "
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    ABSTRACT: The beta-amyloid (Abeta) peptide has been postulated to be a key determinant in the pathogenesis of Alzheimer's disease (AD). Abeta is produced through sequential cleavage of the beta-amyloid precursor protein (APP) by beta- and gamma-secretases. APP and relevant secretases are transmembrane proteins and traffic through the secretory pathway in a highly regulated fashion. Perturbation of their intracellular trafficking may affect dynamic interactions among these proteins, thus altering Abeta generation and accelerating disease pathogenesis. Herein, we review recent progress elucidating the regulation of intracellular trafficking of these essential protein components in AD.
    Full-text · Article · Jan 2014 · Molecular Neurodegeneration
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    • "Presenillins are involved in the trafficking and localisation of a range of metalloproteins including APP, transferrin and tyrosinase [27], [28]. Copper uptake in the midgut of PSN knockdown Drosophila could be reduced as a result of impaired localisation of Ctr1A and Ctr1B. "
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    ABSTRACT: Dietary copper is essential for multicellular organisms. Copper is redox active and required as a cofactor for enzymes such as the antioxidant Superoxide Dismutase 1 (SOD1). Copper dyshomeostasis has been implicated in Alzheimer's disease. Mutations in the presenilin genes encoding PS1 and PS2 are major causes of early-onset familial Alzheimer's disease. PS1 and PS2 are required for efficient copper uptake in mammalian systems. Here we demonstrate a conserved role for presenilin in dietary copper uptake in the fly Drosophila melanogaster. Ubiquitous RNA interference-mediated knockdown of the single Drosophila presenilin (PSN) gene is lethal. However, PSN knockdown in the midgut produces viable flies. These flies have reduced copper levels and are more tolerant to excess dietary copper. Expression of a copper-responsive EYFP construct was also lower in the midgut of these larvae, indicative of reduced dietary copper uptake. SOD activity was reduced by midgut PSN knockdown, and these flies were sensitive to the superoxide-inducing chemical paraquat. These data support presenilin being needed for dietary copper uptake in the gut and so impacting on SOD activity and tolerance to oxidative stress. These results are consistent with previous studies of mammalian presenilins, supporting a conserved role for these proteins in mediating copper uptake.
    Full-text · Article · May 2013 · PLoS ONE
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    • "By cleavage of these substrates, PSs mediate their multiple functions in development, calcium homeostasis, cell adhesion, transport, trafficking/localization, and apoptosis [36,38,50]. FAD-linked PS mutations might impair the γ-secretase-dependent proteolysis of some of the substrates, such as Notch, N-cadherin and tyrosinase, resulting in loss of the related functions of PS [51,52]. Meanwhile, FAD-linked PS mutations might also impair some γ-secretase-independent functions, such as the regulation of β-catenin-dependent signaling [53], modulation of phosphatidylinositol 4,5-bisphosphate metabolism [54], endoplasmic reticulum [Ca2+ leak function [55], PI3K/Akt signaling pathway-dependent neuroprotective roles [56], synaptic homeostasis [57] and fast axonal transport of APP [58]. "
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    ABSTRACT: Alzheimer's disease (AD) is a common neurodegenerative disease characterized clinically by progressive deterioration of memory, and pathologically by histopathological changes including extracellular deposits of amyloid-beta (A-beta) peptides forming senile plaques (SP) and the intracellular neurofibrillary tangles (NFT) of hyperphosphorylated tau in the brain. This review focused on the new developments of amyloid cascade hypothesis with details on the production, metabolism and clearance of A-beta, and the key roles of some important A-beta-related genes in the pathological processes of AD. The most recent research advances in genetics, neuropathology and pathogenesis of the disease were also discussed.
    Full-text · Article · Sep 2012 · Translational Neurodegeneration
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