Shedding light on ocular melanogenesis and pigmentary glaucoma: a narrative review

Introduction

Background

Investigations into melanin synthesis and melanosome development in skin cells are well-established in the literature. However, studies involving pigment-producing cells of the eye remain an area with notable gaps in research and warrant further exploration. Moreover, pigmentary glaucoma (PG) is a disease where aberrant melanogenesis is implicated but not particularly elucidated as a significant contributor to the pathophysiology (1). PG accounts for approximately 1–1.5% of glaucoma cases, predominantly affecting younger, myopic Caucasian males, with a rare incidence reported in Black and Asian populations (2). It is a type of secondary glaucoma where increased posterior bowing of the iris causes an anomalous interaction between the zonular fibers that hold the lens in place and the posterior iris pigment epithelium (IPE) just anterior to the zonular fibers, leading to pigment accumulation in the trabecular meshwork (TM), obstructed aqueous humor (AH) outflow, and subsequent elevations in intraocular pressure (IOP) (3) (Figure 1). This is the primary pathophysiologic mechanism underlying PG, which is why management of PG focuses on reducing posterior bowing of the iris and iridozonular contact through pharmacological agents like pilocarpine and surgical interventions like laser and cataract surgery.

Figure 1 Classical pathophysiological model of pigment dispersion glaucoma. (A) Normal aqueous humor outflow; (B) obstructed aqueous humor outflow in pigmentary dispersion glaucoma; (C) pathogenic mechanisms leading to pigment dispersion (4-7). IPE, iris pigment epithelium; TM, trabecular meshwork.

Nevertheless, this “structural model” is an insufficient description of the full disease pathology, as there is evidence supporting an “IPE dysfunction model” of pigment dispersion syndrome (PDS) and PG caused by pigment epithelium dysfunction and concomitant abnormalities in melanin biosynthesis and melanosome structural integrity (4,8). PDS is speculated to occur secondarily to iris stromal hypovascularity, with histopathologic analysis of iris specimens from patients with classic PG revealing hypopigmented IPE with increased immature melanosomes, suggesting an apparent aberration in melanin synthesis (4,5). Furthermore, mouse models that develop PG are associated with mutations in genes encoding melanosomal proteins (6). Collectively, these findings suggest the pathology of pigment dispersion may lie in melanin-producing cells like the pigment epithelium and is connected to aberrant melanogenesis. This requires us to deepen our understanding of melanogenesis as well as the important key biomolecules that have recognized roles in melanogenesis and glaucoma, like cholesterol, a biomolecule with a well-established role in melanogenesis and glaucoma, making it particularly relevant for focused discussion in the context of this review (Table 1).

Since the primary mechanical iridozonular disease mechanism fails to explain the full spectrum of disease presentations, this paper aims to emphasize and explore previously described associations between melanogenic abnormalities and PDS/PG and examines melanosome development and melanin synthesis pathways to propose a unifying pathological mechanism. We present this article in accordance with the Narrative Review reporting checklist (available at https://aes.amegroups.com/article/view/10.21037/aes-25-28/rc).

Methods

A literature search was conducted using PubMed, Google Scholar, and Web of Science databases to identify relevant English-language publications up to August 2025. Search strategies incorporated both MeSH terms and free-text keywords. The following search terms were used: “ocular melanin”, “melanogenic pathways”, “pigment dispersion”, “melanin metabolism”, “pigmentary glaucoma pathophysiology”, and “cholesterol and glaucoma”. Inclusion criteria encompassed original research articles, clinical studies, case reports, and reviews related to melanogenesis, pigment dispersion, and glaucoma. Animal and human studies were included where they contributed to mechanistic or translational insight. Exclusion criteria included non-English publications and studies without direct relevance to ocular melanogenesis or pigment dispersion mechanisms (Table 2).

Melanosome maturation

Melanosome developmental stages

Melanosomes represent indispensable organelles responsible for melanin production in pigmented cells, exerting their function not only in skin cells but also within ocular structures such as iris stromal cells and the retinal pigment epithelium (RPE). Unlike other conventional cellular organelles, the maturation of melanosomes precludes their functionality. This maturation follows a distinctive morphological progression delineated into stages I to IV, with distinct integral membrane and melanogenic proteins orchestrating specific functions at each developmental stage. Despite melanosomes being categorized as lysosome-related organelles, melanosome maturation entails integration with endocytic pathways as a significant portion of their synthesizing components are derived from early endosomal membranes (7). Early-stage melanosomes (stages I & II) typically exhibit an amelanotic phenotype and are largely responsible for the production, polymerization, and folding of the fibrillar amyloid matrix protein premelanosome protein (PMEL) into fibrils, upon which melanin can be deposited (7,9). Stage I melanosomes represent the most immature melanosomes and are referred to as premelanosomes. Premelanosomal biogenesis involves the invagination of the limiting membrane of coated endosomes which results in the formation of multiple internal membranes or internal luminal vesicles (ILVs) (10). Thus, premelanosomes can also be referred to as multivesicular bodies (MVBs). Premelanosomes have been shown to be mostly derived from endosomal pathways as opposed to the trans-Golgi network (TGN), as evidenced by the presence of an endosomal coat containing early endosomal autoantigen 1 (EEA1) and the endosomal sorting complex required for transport (ESCRT)-0 component Hrs (7). These data support stage I premelanosomes as a transition point between endosomes and fibril-dense stage II premelanosomes. This transition also indicates the role of endosomes over the TGN in early premelanosome organization, with stage I premelanosomes potentially following a more endosomal sorting pathway with an acidic nature (7,9).

PMEL must be transported to early coated endosomes at the beginning of melanosomal biogenesis (Figure 2). PMEL is composed of two linked fragments, Mα and Mβ. The C-terminal Mβ fragment is membrane-integrated, whereas the Mα fragment is the luminal and soluble fragment. Before PMEL undergoes posttranslational processing through the endoplasmic reticulum (ER) and TGN, it is referred to as the P1 form. Once it has been processed, it is then referred to as P2. It is then cleaved by proprotein convertase and migrates towards early-stage melanosomes (MVBs). Following that, it transfers from the limiting membrane to ILVs with the help of tetraspanin (CD63), and the portion proximal to the membrane is cleaved by a metalloprotease of the disintegrin and metalloprotease (ADAM) family and γ-secretase (16). This releases the soluble Mα into the lumen of the melanosome, which is further cleaved into the MαN (N-terminal) and MαC fragment (C-terminal). Both fragments are required for the formation of the characteristic fibrillar amyloid structure of premelanosomes that will later be used for melanin deposition (17).

Figure 2 Pathways of melanosomal protein transport and processing in melanogenesis with cholesterol involvement. Melanosome formation begins at the Golgi apparatus, where PMEL is transported to the early endosome or stage I premelanosome. PMEL cleavage occurs, freeing Mα for fibrillar polymerization (11). PMEL becomes the main structural component as melanosomes mature to stage II. Stage III melanosome requires the BLOC, BLOC-1, BLOC-2, BLOC-3 and AP, AP-3 and AP-1 adaptor complex-mediated TYRP1 and TYR from the Golgi to melanosomes. VAMP7 and VPS33A are involved in the fusion and maturation of melanosomes. Cholesterol implication is marked by the yellow stars. Cholesterol is involved in the sequestration of PMEL17 on cholesterol-dense lipid rafts. Cholesterol facilitates PMEL17 fibrillogenesis and amyloidogenesis in stage II melanosomes. In later stages, cholesterol significantly increases cAMP levels, promoting MITF dependent translation of melanogenic proteins (not shown). Cholesterol metabolism is linked to pathways involved in delivering melanogenic proteins to late-stage melanosomes, protecting tyrosinase and tyrosine hydroxylase from degradation. Additionally, cholesterol interaction with melanoregulin promotes dynein function, aiding in late-stage melanosomal development via melanosome transport. Other genes, such as OCA2 and SLC45A2, are crucial for the transport and processing of melanosomal proteins and melanin synthesis (12-15). AP, activator protein; BLOC, biogenesis of lysosome-related organelles complex; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element binding protein; HOPS, homotypic protein sorting; LM, Limiting membrane; MITF, microphthalmia-associated transcription factor; OCA2, oculocutaneous albinism type 2; PMEL, premelanosome protein; SLC45A2, solute carrier family 45 member 2; SNAREs, soluble N-ethylmaleimide-sensitive factor attachment protein receptors; TYR, tyrosinase; TYRP1, transport of tyrosinase-related protein 1; VAMP7, vesicle-associated membrane protein 7; VPS33A, vacuolar protein sorting-associated protein 33A.

The polymerization of regular, elongated, and striated arrays of the PMEL luminal fragment Mα signifies a transition to stage II as these fibers radiate from the luminal side of ILVs (18). Only the Mα fragment of PMEL is present in stage II premelanosomes, as the Mβ fragment is not essential for fibril formation and is thus removed from subsequent developments (7). Enrichment of PMEL Mα fragment is responsible for the characteristic elongated and ellipsoid appearance of Stage II premelanosomes, as stage II premelanosomes have the highest concentration of PMEL and the highest levels of matrix formation and fibril extension (9,19). The formation of stage II premelanosomes sets the stage for further melanosomal maturation, serving as a transition to later stages of melanosome development and melanin synthesis (7,9). Over the course of stage II development, EEA1 protein levels fall as PMEL levels rise, and protein sorting becomes more specific and melanosome-related as the development separates from endosomal pathways (9).

Melanin synthesis begins in stage III melanosomes, accumulating on the fibrillar structures organized in stage II in increasing concentrations. Detection of PMEL sharply diminishes as activity of the melanogenic enzymes tyrosinase (TYR), tyrosinase-related-protein-1 (TRP1), and dihydroxyphenylalanine (DOPA) chrome tautomerase (DCT) rises rapidly (Figure 3). It should be noted that melanogenic proteins are present in premelanosomes, however, they are effectively inactive by proposed endogenous protease cleavage, and their catalytic functions begin to stabilize in stage II in preparation of melanin synthesis in stage III (9,27,28). The activity of TYR, the rate-limiting enzyme of melanin synthesis, is modulated by: TYRP1 expression, the pH of the organelle it is contained in as it travels from the TGN to the melanosome, and proteasomal activity (29). TYRP1 is a structural melanosome membrane-bound protein and plays a role in stabilizing the TYR complex involved in melanin synthesis and regulates TYR function by acting as a chaperone protein for TYR in the ER (30,31). TYR is suppressed at lower pH while it reaches optimal activity at a more neutral pH, coinciding with the neutralization of melanosomal pH as it becomes less associated with the acidic endosomal pathways and integrates into TGN pathways, resulting in increased pigment production (11,32,33). This integrated model for late-stage melanosome sorting is starkly different from PMEL in premelanosomes, which solely relies on endosomes for its sorting mechanism, and this transition appears to be crucial to providing an environment for melanogenic protein activation and melanin synthesis (9,27).

Figure 3 Protein dynamics across stages of melanosomal maturation. Melanosome maturation proceeds through four defined stages, each marked by distinct morphology and changes in protein expression. In stage I (early endosomes), PMEL is expressed and initiates the pathway toward melanosome development. In stage II (premelanosomes), PMEL continues to be expressed along with MART1, while EEA1 is downregulated; this stage is characterized by the formation of fibrillar structures within the organelle. By stage III, melanin synthesis begins as melanogenic enzymes—TYR, TYRP1, DCT, OCA2, and SLC45A2—are upregulated. In stage IV, continued melanin synthesis is supported by persistent upregulation of these enzymes and structural proteins (6,20-26). DCT, dopachrome tautomerase; EEA1, early endosomal autoantigen 1; OCA2, oculocutaneous albinism type 2; PMEL, premelanosome protein; SLC45A2, solute carrier family 45 member 2; TYR, tyrosinase; TYRP1, transport of tyrosinase-related protein 1.

The last stage of melanosome development (stage IV) sees further melanin accumulation until the maximal possible pigmentation is seen. The concentrations of TRP1 and other melanogenic enzymes continue to increase, revealing a positive correlation between melanosome maturity and melanogenic enzyme level (27,34). The functionality of these melanosomes also becomes specific based on the type and location of the melanocytes. Epidermal melanocytes transfer mature melanosomes to keratinocytes, where they carry out photoprotection and other vital functions (9). This is largely different from retinal and iris-pigmented cells, which do not require transfer from melanosomes, but rather retain highly pigmented melanosomes and utilize them for the purpose of free radical and light management (7).

DBA/2J (D2) mice develop a form of PG due to mutations in the melanosomal protein-encoding genes glycoprotein nonmetastatic melanoma protein B (Gpnmb) and Tyrp1, both of which cause progressive iris disease and depigmentation (6). The Gpnmb gene, expressed in the IPE, encodes the GPNMB protein, a close homolog to PMEL protein, and mutations in this gene are associated with the iris pigment dispersion phenotype of D2 mice (12,35). This is supported by Pmel17 gene variants identified in whole-exome sequencing studies of patients with PDS/PG (8). Like PMEL, Gpnmb plays crucial roles in maintaining the structural integrity of melanosomes and sequestration of cytotoxic intermediates of melanin synthesis. Recent studies have identified mutations in genes like PMEL (13,36) and Gpnmb (20,37) leading to defective melanosome formation, impaired melanocyte function, and release of pigment from the inner plexiform layer, promoting pigment dispersion. PMEL and Gpnmb are known to be important for melanosome structural integrity and containment of cytotoxic melanin synthesis intermediates respectively. Mutations in the Pmel17 allele cause melanosome dysfunction and melanocyte death throughout the body, though it does not cause pigment dispersion (21). Additional neuronal and immune functions important to glaucoma pathology are also associated with Gpnmb (22). The Tyrp1 gene, expressed in the iris stroma, encodes the TYRP1 protein, involved in melanin synthesis in mature melanosomes, and mutations in this gene result in the iris stromal atrophy phenotype in D2 mice (6,23). The mutated gene, Tyrp1^b, causes release of cytotoxic melanin synthesis intermediates from melanosomes, causing melanocyte death, and subsequent iris stromal atrophy (24). A similar mutation of the Tyrp1 gene, Tyrp1^b-lt, results in the light phenotype and directly influences coat color and melanocyte survival in LT/SvEiJ mice (24,25). The oculocutaneous albinism type 2 (Oca2) gene has been identified as a genetic modifier in D2 mice as the OCA2 protein deals with transport and processing of melanosomal proteins like TYRP1 and it regulates pH in melanosomes, supporting the idea of aberrant TYRP1 involvement in melanosomal maturation in PG (38). Though aberrant, continued pigment production appears crucial to pathologic metabolite accumulation in PG, as reduced but not absent pigment production in D2 mice prevented induction of glaucoma, showing dependence on the level of pigment production while showing the propensity for pigment-reducing treatment in PG (6). These data suggest that continued pigment production and accumulation of cytotoxic metabolites of aberrant melanin synthesis contribute to PG in humans.

Pathways for protein sorting and organization

The assortment of melanogenic proteins is complex, involving many signaling proteins. Adaptor protein (AP)-3 is a member of a family of protein complexes that direct intracellular sorting of proteins along the endocytic and secretory pathways, transporting transmembrane proteins to endosomes and lysosomes (39). This role extends to the protein pathways for stage III and stage IV melanosomes, as AP-3 is specifically involved in TYR sorting. Mutations in AP-3 can cause Hermansky-Pudlak syndrome (HPS) types 2 and 10, resulting in the characteristic phenotype of ocular albinism (40). Since AP-3 can associate with clathrin-coated early endosomal buds and is found bound to tyrosine-rich early endosomal buds, it is presumed to play a role in TYR sorting from endosomes (7). This is supported by high concentrations of TYR that appear in early endosomes and MVBs of AP-3 deficient cells. AP-1 also plays a role in TYR sorting, as it maintains TYR activity in HPS type 2 melanocytes by increasing TYR transport in response to AP-3 deficiency (34). Another HPS-like phenotype with defective ocular pigment granules is due to a substitution in the amino acid sequence of the VPS33a subunit of the homotypic protein sorting (HOPS) complex (41). This subunit is a member of a family of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) regulatory proteins, and though its exact role in melanin synthesis is unclear, it may explain HOPS involvement in trafficking TYR-containing endosomes to melanosomes (7,40).

Studies looking into the role that biogenesis of lysosome-related organelles complex 1 (BLOC-1) plays in the transport pathways revealed medium levels of TYR accumulation alongside high levels of TRP1 accumulation in melanocytes with mutant BLOC-1. This is similarly seen in endosomes, indicating that BLOC-1 further utilizes the endosomal pathway (7). Pallidin, a subunit of BLOC-1, has a potential role in vesicle fusion, allowing for proper localization and melanin synthesis. Pallidin also interacts with the SNARE syntaxin 13, with the interaction being central to TRP1 transport (42). Though this is a potential indication that AP-3 and BLOC-1 share sorting pathways, studies show conflicting results, with some showing distinctions in subdomains within the respective pathways and thus indicating an overall different sorting mechanism. Other studies indicate interactions between AP-3 and BLOC-1 for the purposes of CD63 and TRP1 transport, with this interaction being a mechanistic pathway interaction. BLOC-1 and BLOC-2 interactions are also central to late-stage TRP1 transport, playing an important role in melanosome development (7,43).

With BLOC-3’s role in endosomal pathway transport well documented in both pigmented and non-pigmented cells, studies show that this role further extends to recycling SNARE in melanosome-related transport (7). After utilization, SNARE recycling allows for continual melanogenic enzyme transport and a continuing ability for BLOC-3 to regulate the SNARE-transport axis. RAB38 can be utilized alongside BLOC-3 for the purpose of tubule formation, in which vital SNAREs, including VAMP7, can be recycled (44).

The well-defined role of RAB guanosine triphosphate (GTP)ases is in vesicular regulation and transport, with the most significant of these in melanosome-related vesicular transport being RAB-38 and RAB-32. RAB-38 is commonly found across both RPE cells and epidermal melanocytes, with its localization common in vesicular and melanosome structures. This heavily implicates the use of the vesicular pathway mechanism to transport melanogenic enzymes, including TYR and TRP1 (7,45). RAB-32 similarly corroborates this function, with its expression alongside RAB-38 being unique to melanocytes. Studies regarding RAB-38 and RAB-32 deficiency show increased enzyme breakdown and mislocalization within the TGN-vesicle network. Studies regarding OCA2 and solute carrier family 45, member 2 (SLC45A2) show similar effects on melanogenic enzyme transportation (7,17). OCA2/P-deficiency and SLC45A2 deficiency in melanocytes both result in severe mislocalization of TRP1 and TYR alongside changes to melanosome formation, decreasing the formation of stage III and IV melanosomes (7).

Mutations in certain genes that encode proteins involved in protein sorting and trafficking also result in pigment dispersion in mice. For example, the Lyst gene encodes the lysosomal trafficking regulatory protein that deals with the trafficking of early melanosome components (8). The Lyst^bg-j allele is associated with a beige phenotype with dark iris pigmentation and increased melanosome size in mice with the C57BL/6J background (25,46). The exact mechanism for this phenotype is unknown, however, it’s possible that this mutation results in a failure to deliver PMEL to early melanosomes, with a subsequent increase in melanin synthesis and cytotoxic intermediate accumulation, resulting in the pigment dispersion phenotype (25). This disease model gives us further insight into possible pathologic mechanisms that occur in human PDS/PG.

Examining prenatal & neonatal melanosome development

Melanin-producing cells of the eye, like the pigment epithelium and stromal melanocytes, differentiate early in the embryonic eye. In fact, the retinal and iridal pigment epithelium differentiates early in the prenatal period, followed by stromal pigmented cells (47,48). Melanin-producing cells of the eye also have different embryonic origins. The posterior IPE originates from the inner layer of the embryonic optic cup, the RPE, and the anterior IPE from the outer layer of the optic cup, while the uveal melanocytes have neural crest origins (49). Moreover, the majority of melanin synthesis in the RPE occurs during embryonic life and ceases in prenatal animal models (47,50). This contrasts with melanocytes of the skin, which continue to synthesize melanosomes and transport them to nearby keratinocytes throughout an organism’s lifetime. It’s thought that instead of producing new melanosomes, the RPE permanently retains fetal melanized melanosomes, and this is supported by the fact that postnatal RPE cells of the Rhesus monkey lack DOPA reactivity (10,47) (Figure 4). However, melanocytes in the uveal stroma and other areas of pigmented epithelium (excluding RPE) have TYR in addition to the presence of premelanosomes into adulthood, demonstrating continued melanogenesis (50). This is also supported by strongly positive DOPA reactivity of iris stromal melanocytes of the iris in the prenatal period, with continued reactivity into the postnatal period (Figure 4A).

Figure 4 Pigment cell development in the rhesus monkey eyes. (A) Iris stromal melanocytes; (B) choroid stromal melanocytes; (C) anterior iris pigment epithelium; (D) posterior iris pigment epithelium (35,51,52). DOPA, dihydroxyphenylalanine.

The IPE has an anterior and posterior surface, where there exist differences in the developing fetus’s melanosomal maturation and morphology (47). The posterior IPE is generally more uniform, consisting of large and mature melanosomes in fetal and postnatal rhesus monkeys, despite having weak DOPA activity (Figure 4C,4D). In contrast, the anterior IPE of the iris contains more variation in the size and shapes of its melanosomes, and it maintains DOPA activity throughout fetal and postnatal development. It’s hypothesized that the melanosomes of the pigment epithelium may originate in the anterior IPE due to its persistent positive DOPA reactivity when compared to the posterior pigment epithelium (47). Iris stromal melanocytes also have strongly positive and persistent DOPA activity, while choroidal stromal DOPA activity is weak and absent throughout the prenatal and postnatal ages, despite having more mature melanosomes, supporting migration of melanocytes from the iris towards the choroid (Figure 4A,4B).

In light of these data, the iris appears to be a hub for melanosome development, melanin synthesis, and melanosome distribution. Considering PDS/PG, where the pathophysiology is also partially owed to aberrant iridal melanogenesis, we are led to hypothesize that the proposed melanogenic pathology of the disease lies in the improper maturation of posterior IPE melanosomes. This is supported by the widely accepted involvement of the posterior iris in our current mechanical understanding of PG pathology, iridal findings, including hypovascularity and pigment granule shedding in PDS/PG, the presence of large and mature pigmented stage IV melanocytes in the posterior IPE, and the relatively high DOPA-reactivity and melanin synthesis that occurs in the iris stroma and posterior IPE. Additionally, since there are several Pmel17 gene variants in patients with PDS/PG, and PMEL not only plays a role in amyloid matrix formation, but also protects against cytotoxic events, a defective PMEL gene could result in melanosomal dysfunction, melanocyte death, and dispersion of pigment (1,53). Given the presence of inactive melanogenic enzymes in premelanosomes, continued melanosomal maturation and activation of these melanogenic proteins could ensue. Subsequently, synthesis of free melanin pigment and cytotoxic intermediates of melanin production with no PMEL protein scaffold for pigment deposition and sequestration of cytotoxic intermediates could result in their accumulation and melanocyte death (28). This, in combination with aberrant iridozonular rubbing, could explain the release of free pigment granules seen in PDS/PG. Taken together, a likely explanation for the melanogenic pathogenesis of PG lies in the instability and pigment dispersion of free pigment due to cytotoxic intermediate buildup in aberrantly formed late melanosomes devoid of PMEL in the posterior IPE (Figure 5). Given the anterior IPE’s persistent DOPA-reactivity and persistent melanin production crucial to PDS/PG pathology, in addition to the anterior IPEs proposed role in distributing melanosomes to other pigmented epithelial cells, we also hypothesize another explanation involving transfer of anterior IPE melanosomes devoid of PMEL to the posterior IPE, or an aberrant transfer of anterior IPE melanosomes due to cytotoxic metabolite damage in the anterior IPE. More research examining these potential melanogenic causes of pathogenesis in PG could help improve our understanding of this disease and develop mechanism-specific therapeutic solutions.

Figure 5 A hypothetical melanogenic basis for pigment dispersion. Early-stage melanosomes in the IPE begin to form without incorporation of PMEL, a structural protein critical for establishing the fibrillar matrix that stabilizes melanin deposition. As melanosomes mature, melanogenic enzymes—TYR, TRP1, and DCT—become active, driving melanin synthesis. In the absence of a PMEL scaffold, melanin and its reactive CI accumulate, increasing the risk of oxidative stress and cytotoxicity. Over time, this destabilized pigment load compromises IPE cell integrity, leading to cell rupture and the release of free pigment granules. These granules are liberated from the posterior iris and disperse into the anterior chamber, contributing to pigment dispersion and, in some cases, secondary glaucoma (2,6,22,54). CI, cytotoxic intermediates; DCT, dopachrome tautomerase; IPE, iris pigment epithelium; PMEL, premelanosome protein; TRP1, tyrosinase-related protein 1; TYR, tyrosinase.

Pathways for L-DOPA reactivity and melanin production

The amino acid phenylalanine is central to melanin synthesis, playing an intricate role in the formation of L-DOPA (Figure 6). Phenylalanine is primarily converted to L-Tyrosine through phenylalanine hydroxylase (PAH), an enzyme that hydrolyzes the aromatic side chain of the amino acid (26,60). L-tyrosine is further converted to L-DOPA through hydroxylation by TYR, a key melanogenic enzyme. TYR has been noted as distinct from tyrosine hydroxylase through its involvement in melanogenesis, appearing in various rate-limiting steps in melanin synthesis (61). TYR activity itself can be further organized into monophenolase, an activity that involves the conversion of o-monophenols to o-diphenols, and diphenolase, which converts o-diphenols to quinones (61). The hydroxylation of L-tyrosine involves monophenolase activity activated by protein kinase C-β (PKC-β), with diphenolase appearing in the second rate-limiting step of melanin synthesis in which L-DOPA is oxidized to L-DOPAquinone (62,63). The development of melanin, melanosomes, and melanocytes is influenced to a large degree by the expression of microphthalmia-associated transcription factor (MITF), a transcription factor encoded by Mitf gene, that determines the expression of genes related not just to melanocyte differentiation but also to the expression of melanogenic enzymes (64). The involvement of the cyclic adenosine monophosphate (cAMP) signaling pathway has been noted to regulate MITF expression, impacting melanin development tangentially. The pathway begins with the binding of the α-melanocyte-stimulating hormone (α-MSH) to the melanocortin 1 receptor (MC1R), activating cAMP (65,66). cAMP, in turn, activates cAMP-dependent protein kinase A (PKA) by binding to its subunits, leading to activated PKA, which can phosphorylate cAMP response element-binding protein (CREB) (65,67). CREB is central for MITF activation, directly impacting enzyme activity and presence within the melanin synthesis process (51,68,69). CREB binds to the M-MITF promoter, with M-MITF being specific to melanocyte development and melanogenesis. By phosphorylating CREB, the cAMP pathway, in turn, is able to upregulate M-MITF and the expression of melanogenic enzyme genes (51,68,69).

Figure 6 The Raper-Mason pathway for melanin synthesis. This pathway begins with the conversion of phenylalanine into L-tyrosine and then to L-DOPA by tyrosinase. L-DOPA is further processed into L-DOPA quinone, leading to two distinct pathways: one producing eumelanin via DHI and DHICA intermediates, and the other producing pheomelanin through cysteinyl DOPA and its oxidation products. Intermediates of melanin synthesis, like L-DOPA, the DHICA intermediate DAI (not shown), DHI, and other ROS, are melanin precursors/intermediates with inherent cytotoxicity (shown in red). The final melanin pigments are stored on the PMEL scaffold within melanosomes (55-59). DAI, 5,6-dihydroxyindole ; DCT, dopachrome tautomerase; DHI, 5.6-dihydroxyindole; DHICA, 5,6-dihydroxyindole-2- carboxylic acid; DOPA, dihydroxyphenylalanine; PAH, phenylalanine hydroxylase; ROS, reactive oxygen species; TRP1, tyrosinase-related-protein-1.

Intersection of cholesterol and melanogenic pathways

Cholesterol has been demonstrated to be involved in the pathophysiology of primary open-angle glaucoma (POAG) (70). Cellular lipids modulate TM plasma membrane remodeling and stiffness, signal transduction cascades, and actin cytoskeleton-cell adhesions linked to the extracellular matrix (ECM) of the TM (52). In fact, cyclic mechanical stress on the TM alters lipid contents and increases cholesterogenic enzymes like squalene synthase, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) synthase, and sterol regulatory element-binding protein 2 (SREBP2) in human cells, resulting in downstream lipogenesis. Additionally, Rho GTPase regulates alterations in cell-ECM interactions, which increase TM tensile nature and decrease outflow. Isoprenylation of Rho GTPase results in increased actinomyosin contractile activity and ECM synthesis/assembly (54). Statins can inhibit isoprenylation by disrupting the membrane-associated Rho GTPase, decreasing ECM contractility, and providing further support for the role of cholesterol in POAG. Given cholesterol’s active role in the pathophysiology of POAG, it is worth reviewing cholesterol’s role in melanogenesis in light of PG and its melanogenic implications (Figure 2).

In early melanosomes

Amelanotic cells exhibit higher cholesterol content, suggesting that early melanosomes may have an increased dependency on cholesterol (55). MVBs contain a unique cohort of “raft-like” lipids associated with ILVs. The lipids that comprise these rafts are particularly comprised of ceramide, glycosphingolipids, and cholesterol. In fact, melanosomal ILV raft lipids are rich in cholesterol and are implicated in playing a role in enhancing PMEL fibrillogenesis and amyloidogenesis (18,56). They are involved in the sequestration of PMEL on ILVs, which precedes and facilitates the liberation of the amyloidogenic Mα fragment by proprotein (prohormone) convertase, which is found in the luminal domain of ILVs, all of which is crucial for fibril formation in stage II. Cholesterol continues to be involved in facilitating the conformational changes required for amyloidogenesis from folded PMEL. Though the exact mechanism is unknown, it is speculated that lipid rafts enhance conformational changes needed for amyloidosis of PMEL, like amyloidosis in other disease processes involving amyloid, like Alzheimer’s and Prion disease (18,57). Raft-like structures are required for the processing of Alzheimer’s precursor protein to amyloidogenic peptide (Aβ peptide) (58). Lipid-protein interaction via lipid rafts in prion disease induces aggregation and fibrillization by inducing increased ordering of conformational changes (unfolding of terminal prion segment) (59).

In late melanosomes

Cholesterol also has roles in late-stage melanosome development and melanin synthesis. Many signaling molecules are implicated in melanogenesis, like α-MSH, adrenocorticotropic hormone, and estrogen. However, cholesterol provides a quick, biphasic, and potent translational level signal for melanin synthesis (55). Cholesterol owes its potency to the secondary messenger cAMP, as it has demonstrated the ability to significantly increase cAMP levels in melanocytes and subsequent translation of melanogenic proteins involved in late-stage melanosomes (MITF, TYP, TRP1) (55) (Figure 2). Contrarily, inhibition of melanogenesis through methyl-β-cyclodextrin-mediated cholesterol reduction has demonstrated the inhibition of melanogenesis and MITF downregulation (71). Due to cholesterol’s ability to stabilize membranes and its presence in melanosomes, it may provide additional protection to the crucial melanogenic enzymes TYR and tyrosine hydroxylase and protect these enzymes from proteasomal degradation (55). Assuming that the ocular cholesterol is mostly derived de novo from HMG-CoA reductase (HMGCAR), as it is in the mouse retina (72), it seems logical to believe that statin drugs, pharmacotherapy that inhibits cholesterol synthesis, would result in decreased melanogenesis. However, the literature contains controversial studies showing some statins increase melanogenesis while others have decreased melanogenesis (73-76). This could be owed to enhanced TYR activity from a statin-induced increase in α-MSH, as demonstrated by fluvastatin (73). Mevastatin, a more potent statin, has been shown to inhibit melanin production by not only inhibiting the translation of melanogenic proteins but also inhibiting α-MSH-induced cAMP-mediated melanogenesis. This points to α-MSH as being a possible key mediator of effective statin-mediated melanogenesis inhibition. Of note, other lipid-lowering drugs that further the interconnection between cholesterol and melanogenesis, like artemisinic acid and diallyl-disulfide analog, suppress cAMP-PKA signaling and inhibit CREB-DNA binding, respectively (75,77). The effects of cholesterol-modifying drugs on ocular melanin homeostasis and whether such effects ultimately mitigate or exacerbate the cytotoxic melanogenic dysregulation hypothesized in PG remain unclear. Given the biological plausibility and widespread use of statins, further investigation into their role in PG pathogenesis and potential therapeutic utility is well warranted.

Pathways that involve the delivery of melanogenic proteins to late-stage melanosomes are also linked to cholesterol metabolism. HPS is a protein that is defective in HPS, yet is also involved in the transport of intracellular cargo to lysosomes and lysosome-related proteins like melanosomes. It has many subtypes, with the HPS6 subtype resembling a BLOC-2 deficiency (40). This deficiency results in the failure of crucial melanogenic proteins TYR and TYRP1, delivered to the melanosome, leading to the characteristic oculocutaneous albinism seen in patients. HPS appears to have a relation to cholesterol since HPS1 variants in mice have been shown to be atherogenic due to increased cholesterol levels (78). HPS-deficient lysosomes have an associated increase in mammalian target of rapamycin (mTOR), which controls transcription factor SREBP, a master regulator for low-density lipoprotein receptor (LDLR) and HMGCAR too (14). This is increased in HPS1 knockouts. mTOR is able to strengthen the internalization of low-density lipoprotein (LDL) and reduce degradation. Rab32 localizes mTOR to lysosomes. It’s hypothesized that HPS dictates the localization of Rab32 to different cellular compartments, but in its absence, Rab32 preferentially localizes mTOR to lysosomes, resulting in increased lipidogenesis (14). This demonstrates that proteins of melanosomal protein pathways are linked to cholesterol metabolism, however, their implications in melanin synthesis require further investigation.

Cholesterol’s interaction with melanoregulin is another potential intersection of cholesterol in melanosome development. Melanoregulin is a melanosome membrane protein involved in microtubule-based transport of late endosomes/lysosomes via dynein activity. Melanoregulin has a cholesterol recognition sequence motif (CRAC motif) that promotes dynein function when bound (15). Cholesterol, therefore, has early involvement in melanosomal development as a signaling molecule; it continues to aid in melanosomal development in later stages as well. However, this process only appears in epidermal melanocytes, whereas stage IV melanosomes in pigmented cells of the eye are retained rather than transported (7,79). Further characterization of melanogenesis and the biomolecules that may be implicated may aid in increasing the understanding of the aberrant melanogenesis that occurs in PDS/PG.

Prostaglandins are molecules produced from arachidonic acid from membrane phospholipids and are widely implicated in inflammatory mediation. Topical analogs are regularly used therapeutically in the treatment of glaucoma as IOP-lowering pharmacotherapy. Prostaglandins have also demonstrated propensity to influence cholesterol metabolism and melanin synthesis, and are thus speculated to have therapeutic possibilities in PDS/PG (1). This is in accordance with the presence of prostaglandin F receptors (FP) in iris stroma and smooth muscle, and the increase in iris melanin synthesis attributed to the topical prostanoids latanoprost and travaprost (80,81). Prostaglandin analogues like prostaglandin E1 (PGE1), prostaglandin E2 (PGE2), and iloprost have demonstrated the ability to improve cholesterol metabolism in the liver and inhibit cholesterol synthesis in mononuclear leukocytes. However, given that cholesterol synthesis in the eye is primarily presumed to be de novo, the influence of prostaglandins on HMG-CoA reductase is of interest. The prostaglandin analog, cyclopentenone prostaglandin A2 (PGA2), has been shown to inhibit HMG-CoA reductase (82). Since PGA2 inhibits HMG-CoA reductase through a mechanism of action different from statins, PGA2 may reduce cholesterol-mediated melanin synthesis, serving as a possible therapeutic in PDS/PG with superior effectiveness when compared to statins and their variable melanogenic response (1).

Strengths and limitations

This review aims to synthesize existing literature and present a novel perspective on the role of melanogenesis in the pathogenesis of PDS and PG. One of the primary strengths of this work is its focus on a disease mechanism that remains largely underrecognized in the field. By integrating data from classic studies in rhesus monkeys with more recent findings on melanin and cholesterol, the paper offers a cohesive framework that connects previously disparate areas of research. While many of the foundational studies cited are dated, they are methodologically sound and remain relevant, providing an important basis for the proposed melanogenic hypothesis. Additionally, the visual figures and schematics were carefully designed to distill complex pathways into accessible diagrams, helping to illustrate connections that may not be immediately apparent from the literature alone. Nevertheless, there are several limitations that warrant consideration. This manuscript is a narrative review rather than a systematic one. While we did not follow a formal protocol with prespecified inclusion and exclusion criteria, we conducted a targeted and search of the PubMed database using a combination of disease-specific and molecular search terms to capture relevant primary research and reviews. A summary of this approach has been included in the abstract to improve transparency. We also acknowledge that fewer than 20% of the references cited are from the past three years. While this reflects the true scarcity of recent work in this area, it nonetheless limits the review’s temporal scope. Lastly, several of the proposed links extrapolate between biological systems in a way that, while theoretically grounded, still requires further empirical validation.

Conclusions

Conditions like pigment dispersion glaucoma (PG) suggest that aberrant melanogenesis plays a significant role in their pathophysiology, necessitating a deeper understanding of melanin biogenesis in ocular cells to develop improved hypotheses and research. This is emphasized by the presence of ocular diseases marked by disruptions in melanogenesis and melanosome development, such as ocular albinism, HPS, and Niemann-Pick disease. By utilizing data from melanin synthesis and fetal and postnatal melanosome development and integrating this with clinical and histopathologic PDS/PG data, we hypothesize an additional pathogenic explanation involving abnormal IPE melanosome development. Comprehensive investigations into other biomolecules associated with melanogenesis, like melatonin, which has also been implicated in melanin synthesis, are essential. This review highlights the intricate interplay of cholesterol in melanogenic pathways and its relation with IOP regulation and glaucoma, providing depth to our knowledge of ocular melanogenesis. However, this review also reveals many gaps in the body of literature discussing ocular melanogenesis, underscoring the need for more research to fill these gaps. Though we acknowledge that this may not provide an exhaustive review of the literature, improving our understanding of ocular melanogenesis may better help us bridge gaps in the literature and offer new perspectives on ocular pigment-related disease processes and potential therapeutic targets.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://aes.amegroups.com/article/view/10.21037/aes-25-28/rc

Peer Review File: Available at https://aes.amegroups.com/article/view/10.21037/aes-25-28/prf

Funding: This work was supported by NIH (Nos. EY031292 and EY14801 to S.K.B.), an unrestricted grant from Research to Prevent Blindness (No. GR004596-1 to S.K.B.) and Miami Metabolomics Research Support Group.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aes.amegroups.com/article/view/10.21037/aes-25-28/coif). S.K.B. serves as an unpaid editorial board member of Annals of Eye Science from August 2024 to December 2026. S.K.B. serves as an unpaid chair of Medical School Faculty Council of University of Miami and serves as an unpaid member of the board of trustees of AOPT till 2023. S.K.B. serves as an unpaid editorial board member of PLOS one. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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