Let There Be Sunlight—Melanogenesis as a Model for AD?

Planning on taking a break from research by relaxing on a nice warm beach? Be advised, by the time you finish reading this story the pathology that goes on in AD and other amyloidoses may follow you to the beach. In work described by Gunnar Gouras, Cornell University, New York, as akin to “peering into neurons of the AD brain as amyloid pathology gets underway,” researchers led by Graça Raposo, Institut Curie, Paris, France, report on melanogenesis in an upcoming paper in PNAS online. At its heart lies the formation of β-sheet fibrils comprising a fragment of an integral membrane protein. The parallels to amyloidoses in general, and amyloid-β (Aβ) fibrillogenesis in particular, are curious. And if that’s not enough to get your attention, the researchers show that the process takes place in multivesicular bodies (MVBs), which Gouras and others propose to be a major site for Aβ precursor protein processing. “The same processes that regulate melanogenesis might also regulate pathological amyloid fibrils,” suggested Raposo in an interview with ARF. Her work begs the question whether Aβ fibrillogenesis goes on in MVBs, and whether the tools she used to detect fibrils in melanocytes might reveal intraneuronal Aβ fibrils in neurons, as well.

That functional, non-pathological amyloids exist has been known for some time. In 2005, researchers led by Jeffery Kelly at Scripps Research Institute in San Diego, California, reported that amyloid fibers of the integral membrane protein, Pmel17, accumulate in melanosomes (see ARF related news story). The fibers bind Congo red and thioflavin S, two amyloidophilic dyes commonly used to detect Aβ deposits in brain tissue. But how and where these melanosome fibrils form was unclear. Now, using high pressure freezing (HPF) to rapidly preserve tissue and a form of microscopy called double tilt 3D electron tomography, Raposo and colleagues have peered into melanocytes to show that Pmel17 amyloid-like fibrils begin to form in MVBs and are fully formed into β-sheet like arrays in the melanosomes.

First author Ilse Hurabin and colleagues characterized melanogenesis in a pigmented melanoma cell line called MNT-1. These cells produce melanosomes in all four described stages of maturation. With HPF and the 3D tomography, Hurabin was able to show that the Pmel17 amyloid fibrils form in non-pigmented stage II melanosomes. The fibrils, which appear as separate tubules in two-dimensional snapshots, are actually revealed as being continuous in one plane by 3D tomography, indicating that they assemble into sheets, just like other amyloids (see movie below). The researchers found that the earliest signs of fibrillogenesis occur in MVBs containing one to four internal vesicles. The amyloid fibrils are closely associated with these vesicles, particularly the larger ones, and as the fibrils grow, the vesicles shrink. This concomitant dynamic appears to be related to maturation of melanosomes.

 

Amyloid fibrils in multivesicular bodies
This 3D reconstruction shows that amyloid fibrils of the Pmel17 protein form in multivesicular bodies in MNT-1 melanoma cells. 3D tilt tomography shows that the fibrils form sheets and are closely associated with intraluminal vesicles. More movies are available as supplementary information on the PNAS website. [Movie copyright: National Academy of Sciences]

It is not clear if amyloid formation in melanosomes relates to Aβ fibrillogenesis, but the authors suggest that the processes may be similar. They describe some interesting parallels. Pmel17, for example, is first cleaved by a proteolytic pro-hormone convertase to yield a smaller Mα fragment, which appears to be the fibrillogenic form. Cleavage of the type II membrane protein BRI2 by furin, a member of the pro-hormone convertase family, is a necessary step in generating the ABri and ADan amyloids that cause familial British and Danish dementias, respectively (see ARF related news story). MVBs may also be a common link. Aβ reportedly accumulates in these organelles (see Takahashi et al., 2002), and some of them mature into exosomes, which Raposo and colleagues have linked to release of pathogenic prions from the cell (see Fevrier et al., 2004). Kai Simons and colleagues at Max Planck Institute in Dresden, Germany, have reported a similar export route for Aβ (see ARF related news story). “My feeling is that these MVBs are providing a favorable environment for amyloid fibril formation,” said Raposo. “They are slightly acidic and their intra-luminal vesicles are lipid raft-like.” Lipid rafts have been linked to amyloidogenesis via both γ- and β-secretase activity.

“We have many parallel research directions in AD that relate to this work, including the role of autophagy, SorLA, lipid/ApoE biology, synaptic dysfunction, protein aggregation, among others,” said Gouras. Next time you are floating on a raft catching some rays, spare a thought for melanogenesis and how it might offer clues to Aβ fibrillogenesis.—Tom Fagan

Comments

  1. I recommend the primary paper.

    View all comments by J. Lucy Boyd

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References

News Citations

  1. Is It Good for You? Amyloid Shows New Side in Mammalian Cells
  2. BRIdging Alzheimer Disease and British/Danish Dementias
  3. Chew ’em Up and Spit ’em Out: Aβ Leaves Cells via Exosomes

Paper Citations

  1. Takahashi RH, Milner TA, Li F, Nam EE, Edgar MA, Yamaguchi H, Beal MF, Xu H, Greengard P, Gouras GK. Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am J Pathol. 2002 Nov;161(5):1869-79. PubMed.
  2. Fevrier B, Vilette D, Archer F, Loew D, Faigle W, Vidal M, Laude H, Raposo G. Cells release prions in association with exosomes. Proc Natl Acad Sci U S A. 2004 Jun 29;101(26):9683-8. Epub 2004 Jun 21 PubMed.

External Citations

  1. PNAS

Further Reading

Primary Papers

  1. Hurbain I, Geerts WJ, Boudier T, Marco S, Verkleij AJ, Marks MS, Raposo G. Electron tomography of early melanosomes: implications for melanogenesis and the generation of fibrillar amyloid sheets. Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19726-31. PubMed.

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