PMEL Amyloid Fibril Formation: the Bright Steps of Pigmentation

International Journal of Molecular Sciences Review PMEL Amyloid Fibril Formation: The Bright Steps of Pigmentation Christin Bissig 1,2,†, Leila Rochin 3,† and Guillaume van Niel 1,2,* 1 Institut Curie, Paris Sciences et Lettres Research University, UMR144, Centre de Recherche, 26 rue d’ULM, Paris F-75231, France; [email protected] 2 Centre National de la Recherche Scientifique, UMR144, Paris F-75248, France 3 Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3BX, UK; [email protected] * Correspondence: [email protected]; Tel.: +33-156-246-442 † These authors contributed equally to this work. Academic Editor: Manickam Sugumaran Received: 22 June 2016; Accepted: 22 August 2016; Published: 31 August 2016 Abstract: In pigment cells, melanin synthesis takes place in specialized organelles, called melanosomes. The biogenesis and maturation of melanosomes is initiated by an unpigmented step that takes place prior to the initiation of melanin synthesis and leads to the formation of luminal fibrils deriving from the pigment cell-specific pre-melanosomal protein (PMEL). In the lumen of melanosomes, PMEL fibrils optimize sequestration and condensation of the pigment melanin. Interestingly, PMEL fibrils have been described to adopt a typical amyloid-like structure. In contrast to pathological amyloids often associated with neurodegenerative diseases, PMEL fibrils represent an emergent category of physiological amyloids due to their beneficial cellular functions. The formation of PMEL fibrils within melanosomes is tightly regulated by diverse mechanisms, such as PMEL traffic, cleavage and sorting. These mechanisms revealed increasing analogies between the formation of physiological PMEL fibrils and pathological amyloid fibrils. In this review we summarize the known mechanisms of PMEL fibrillation and discuss how the recent understanding of physiological PMEL amyloid formation may help to shed light on processes involved in pathological amyloid formation. Keywords: melanosome; PMEL; amyloid; pigmentation; fibril formation; melanocyte; secretases; apolipoprotein E 1. Introduction In vertebrates, pigment cells synthesize and store melanin pigment in lysosome-related organelles (LRO) called melanosomes. Melanin synthesis results from a complex sequence of chemical reactions that is initiated by the conversion of L-tyrosine in dopaquinone by a key enzyme, Tyrosinase. After the formation of dopaquinone, distinct pathways of synthesis lead to the generation of the red and yellow pheomelanins or the black and brown eumelanins [1]. Major modulator of melanin synthesis and switch from eumelanin to pheomelanin are intrinsic and extrinsic factors [2] that regulate notably gene expression [3–5] of melanogenic factors. However, different events of endomembranes and vesicle trafficking in pigment cells also tightly regulate melanin and melanosome production [6]. As a consequence, melanosomes synthesizing predominantly eumelanin or pheomelanin have distinct contents and morphology. Eumelanosomes that synthesize mostly eumelanin have a characteristic ellipsoidal shape due to the accumulation of intraluminal fibrils. In this review, we will focus on the formation of these intraluminal fibrils in eumelanosomes, which we call hereafter melanosomes. These fibrils are often referred to as “the melanosome matrix” [7,8] and arise from the proteolytic processing of the pre-melanosomal protein (PMEL) that is also called Pmel17, gp100 or Silver in mice. Int. J. Mol. Sci. 2016, 17, 1438; doi:10.3390/ijms17091438 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2016, 17, 1438 2 of 14 Int.arise J. Mol.from Sci. the2016 ,proteolytic17, 1438 processing of the pre-melanosomal protein (PMEL) that is also called2 of 14 Pmel17, gp100 or Silver in mice. PMEL fibrils are a major functional component of the melanosomal PMELcompartment fibrilsare as they a major optimize functional melanin component polymerization, of the melanosomal condensation compartment and storage [9]. as they optimize melaninPMEL polymerization, fibrils have an condensation amyloidogenic and nature storage and [9 ].share features with pathological amyloids [10]. VariousPMEL proteins fibrils haveform anamyloid amyloidogenic fibrils in nature the context and share of featurespatholog withies such pathological as neurodegenerative amyloids [10]. VariousAlzheimer’s proteins and Parkinson’s form amyloid diseases fibrils [11]. in the Howeve contextr, more of pathologies recently, the such concept as neurodegenerative of physiological Alzheimer’samyloids has and emerged Parkinson’s and PMEL diseases fibrils [11 represent]. However, the morefirst physiological recently, the conceptamyloids of that physiological have been amyloidsdescribed hasin humans emerged [10,12]. and PMEL It is expected fibrils represent that understanding the first physiological the different amyloids mechanisms that underlying have been describedoptimal formation in humans of [physiological10,12]. It is expected PMEL fibrils that understanding will help to understand the different the mechanismsprocesses leading underlying to the optimalformation formation of pathological of physiological amyloids. PMEL Indeed, fibrils to willavoid help any to toxicity understand potentially the processes associated leading with to the formationformation of amyloids, pathological the amyloids. fibrillation Indeed, of PMEL to is avoid tightly any regulated toxicity by potentially different associatedevents that with involve the formationPMEL traffic, of amyloids, cleavage theand fibrillation sorting into of PMELearly me is tightlylanosomal regulated (premelanosoma by differentl) eventscompartments that involve [9]. PMELHowever, traffic, mutations cleavage in PMEL and sorting that affect into PMEL early oligomerization melanosomal (premelanosomal) and fibrillation render compartments physiological [9]. However,PMEL amyloid mutations formation in PMEL pathogenic that affect [13]. PMEL Thus, oligomerization PMEL amyloidogenesis and fibrillation can render be considered physiological as a PMELphysiological amyloid reference formation to shed pathogenic light on [13 unexpe]. Thus,cted PMEL mechanisms amyloidogenesis that may be can compromised be considered under as a physiologicalpathological situations reference and to shed lead lightto pathological on unexpected amyloidogenesis. mechanisms that may be compromised under pathologicalMelanosomes situations mature and leadthrough to pathological four different amyloidogenesis. stages that can be divided into two main steps (FigureMelanosomes 1) [6,14–16]. mature The unpigmen throughted four step different comprises stages the thatgeneration can be of divided stage I intoand twoII melanosomes main steps (Figurethat are1 )[referred6,14–16 as]. immature/premelanosomal The unpigmented step comprises compartments, the generation whereas of stagethe pigmented I and II melanosomes step allows thatthe arematuration referred asof immature/premelanosomalstage II into stage III and compartments, IV melanosomes whereas that theare pigmented denoted as step mature/late allows the maturationcompartments. of stage Melanogenesis II into stage IIIrequires and IV melanosomesmorphological that and are functional denoted as modification mature/late compartments.of endosomal Melanogenesiscompartments, requireswhere PMEL morphological fibril formation and functional is initiated. modification PMEL fibrils of endosomalstart to nucleate compartments, in stage I wheremelanosomes PMEL fibrilthat correspond formation is to initiated. multivesicular PMEL endosomes fibrils start (MVEs) to nucleate characterized in stage I melanosomesby the presence that of correspondintraluminal to vesicles multivesicular (ILVs), endosomesa clathrin coat (MVEs) at the characterized cytosolic side by theand presence the absence of intraluminal of melanin vesicles[14]. In (ILVs),stage I amelanosomes, clathrin coat atPMEL the cytosolic is cleaved side and and its the luminal absence domain of melanin is sorted [14]. onto In stage ILVs I promoting melanosomes, the PMELnucleation is cleaved of fibrils. and Stage its luminal II melanosomes domain is are sorted characterized onto ILVs by promoting the absence the nucleationof pigment ofand fibrils. the Stagepresence II melanosomes of PMEL fibrils are organized characterized into byparallel the absence sheets ofthat pigment elongate and the the compartment. presence of PMELThese fibrilsfibrils organizedserve as a into matrix parallel for sheets melanin that elongatesynthesis, the which compartment. starts in These stage fibrils III servemelanosomes. as a matrix In for stage melanin IV synthesis,melanosomes, which melanin starts in synthesis stage III melanosomes.reaches its paroxysm In stage and IV melanosomes, results in the melanincomplete synthesis masking reaches of the itsfibrils paroxysm [6]. Here, and we results present in the the main complete steps maskingregulating of PMEL the fibrils fibril [ 6formation]. Here, we and present discuss the the main relevance steps regulatingof this amyloid PMEL structure fibril formation in pigmentation and discuss and the relevanceits potential of this use amyloid as a reference structure model in pigmentation to better andunderstand its potential pathological use as a referenceamyloidogenesis. model to better understand pathological amyloidogenesis. Figure 1.1. SchematicSchematic representationrepresentation of of melanosome melanosome biogenesis. biogenesis. The The different different stages stages

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