Wang R, Tang P, Wang P, Boissy RE, Zheng H. Regulation of tyrosinase trafficking and processing by presenilins: partial loss of function by familial Alzheimer's disease mutation. Proc Natl Acad Sci U S A. 2006 Jan 10;103(2):353-8. PubMed.

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  1. The lack of pigmentation in the presenilin mutants is a very interesting and potentially very important finding. It raises the question of what the molecular basis for the dysfunctional melanosomes could be. While the appearance of tyrosinase cleavage fragments upon presenilin inhibition is a useful molecular marker, it is unclear how this relates to the trafficking defect observed; indeed, it would seem more likely to be a consequence of tyrosinase mistrafficking rather than a cause. Cleavage of a vesicle "cargo" protein would be unlikely to cause the accumulation of vesicles. Moreover, it is unclear how loss of presenilin proteolytic activity would lead to increased proteolytic cleavage of tyrosinase. Thus, the mechanistic link between presenilin activity and melanosome targeting remains to be solved.

    While cleavage of the pigment cell-specific protein Pmel17 by a proprotein convertase is necessary for amyloidogenesis and formation of the fibrous melanosome matrix, to my knowledge there is no link between presenilins and Pmel17 trafficking or processing. Moreover, we know from unpublished work on the mouse silver mutant that a deficiency of Pmel17 has no effect on the segregation of melanosomes from endosomes/lysosomes or on the targeting of late melanosome cargo like tyrosinase, Tyrp1, or DCT, as Wang et al. see in their PS1-deficient cells. The one potential link between Pmel17 and presenilins may be the fate of the small, membrane-bound Mβ cleavage fragment after the larger lumenal Mα fragment undergoes amyloidogenesis. We know that we can partially stabilize Mβ in melanocytic cells by treatment with lysosomal protease inhibitors (unpublished data), but the effect is not dramatic. Thus, it is quite possible that presenilins have something to do with the elimination of this fragment. However, images shown in Wang et al. suggest that while such an activity of presenilins may facilitate optimal Mα amyloidogenesis, it is not likely to be required. The appearance of relatively intact stage II melanosomes would argue against a requisite role for PS1/2 activity in the Pmel17 life cycle.

    It is perhaps surprising that the authors did not note the morphological similarity of PS1-deficient cells with another pigmentation mutant, the p or OCA2 mutation. P encodes a 12-transmembrane domain protein with similarity to bacterial anion permeases, and some evidence suggests that it localizes to melanosomes. P-deficient (OCA2) melanocytes show defective maturation and trafficking of tyrosinase and Tyrp1, nearly complete lack of pigmentation, and slightly smaller stage II melanosomes as observed upon inhibition of PS1 (for review, see Brilliant, 2001). They also show abnormalities in compartmental pH regulation, which may have a more direct effect on the specialization of the endocytic pathway needed to maintain cargo segregation for melanosome biogenesis (Raposo et al., 2001). Indeed, I find the similarity of PS1-deficient cells with OCA2 cells much more striking than that with the HPS3 cells noted by the authors. P is one of a growing list of ion permeases/transporters that are gaining increasing notoriety for their role in pigmentation, including the underwhite/OCA4 gene (Newton et al., 2001) and more recently SLC24A5 (Lamason et al., 2005). If I were to guess, it may be regulation of one of these critical proteins that is the major target of PS1/2 activity in melanocytes. Of course, it is also highly possible that the target is a SNARE protein or some other regulator of membrane fusion (Chen and Scheller, 2001), but it would be harder to imagine how a defect in such a target would not also cause problems with many other cell types in the conditional knockout.

    References:

    Brilliant MH. The mouse p (pink-eyed dilution) and human P genes, oculocutaneous albinism type 2 (OCA2), and melanosomal pH. Pigment Cell Res. 2001 Apr;14(2):86-93. PubMed.

    Raposo G, Tenza D, Murphy DM, Berson JF, Marks MS. Distinct protein sorting and localization to premelanosomes, melanosomes, and lysosomes in pigmented melanocytic cells. J Cell Biol. 2001 Feb 19;152(4):809-24. PubMed.

    Newton JM, Cohen-Barak O, Hagiwara N, Gardner JM, Davisson MT, King RA, Brilliant MH. Mutations in the human orthologue of the mouse underwhite gene (uw) underlie a new form of oculocutaneous albinism, OCA4. Am J Hum Genet. 2001 Nov;69(5):981-8. PubMed.

    Lamason RL, Mohideen MA, Mest JR, Wong AC, Norton HL, Aros MC, Jurynec MJ, Mao X, Humphreville VR, Humbert JE, Sinha S, Moore JL, Jagadeeswaran P, Zhao W, Ning G, Makalowska I, McKeigue PM, O'donnell D, Kittles R, Parra EJ, Mangini NJ, Grunwald DJ, Shriver MD, Canfield VA, Cheng KC. SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans. Science. 2005 Dec 16;310(5755):1782-6. PubMed.

    Chen YA, Scheller RH. SNARE-mediated membrane fusion. Nat Rev Mol Cell Biol. 2001 Feb;2(2):98-106. PubMed.

    View all comments by Michael S. Marks

  2. Remarkable advances in understanding the pathobiology and mechanisms of neurodegeneration in AD over the past 20 years have engendered realistic hopes for the discovery of more meaningful and effective new drugs to treat AD. Based on these advances, most targets of drug discovery for AD focus on gains of toxic functions by amyloid deposits in AD such as those formed by fibrillar species of tau and Aβ. There is intense interest in Aβ-focused drug discovery efforts; most attempt to block or reverse Aβ plaque formation, or eliminate excess accumulations of Aβ oligomers and fibrils or aggregates of these pathological forms of Aβ.

    Nonetheless, the onset and progression of AD also could result from loss-of-function abnormalities affecting tau or Aβ. When these proteins misfold, oligomerize, and fibrilize to form amyloid filaments and aggregate, the theory goes, they are sequestered and unable to perform their normal functions. However, a detailed understanding of the normal functions of Aβ, its precursor protein, as well as the presenilins required for γ-secretase cleavage of Aβ is still not available, and this limits drug discovery efforts that target losses of functions in these proteins that might contribute to disease pathogenesis.

    Thus, the importance of this paper lies in bringing into sharper focus the functions of the presenilins by implicating them in tyrosinase processing and trafficking. While the repercussions of impairments in these presenilin functions in the brain, and especially in neurons, will need to be examined further, the study opens up new avenues of research into mechanisms of AD and new possibilities for AD drug discovery.

    View all comments by John Trojanowski

  3. I believe this reductionist finding will have important implications for future molecular research into melanin transport. This could thus lead ultimately to new clinical treatment modalities for deficient genetic pigment manufacture. However, this will not lead to a new way to fight the battle against A.D. We are nowhere near the ability to do genetic reprogramming on such a grand scale. The ramifications of genetic tinkering in the way that would be necessary to apply these research findings is more than 15 years away in my opinion.

    View all comments by Jacob Mack

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  1. Mouse of a Different Color: Presenilin Mutations Affect Melanin