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BACE2 processes PMEL to form the melanosome amyloid matrix in pigment cells

Leila Rochin1, Ilse Hurbain, Lutgarde Serneels

  • 1Institut Curie, and Unité Mixte de Recherche 144, Centre National de la Recherche Scientifique, F-75248 Paris, France.

Proceedings of the National Academy of Sciences of the United States of America
|June 12, 2013
PubMed

Insights

Beta-site APP cleaving enzyme 2 (BACE2) processes Melanocyte Protein (PMEL) to create functional amyloids. This reveals BACE2

Area of Science:

  • Biochemistry
  • Cell Biology
  • Genetics

Background:

  • Amyloids are linked to diseases like Alzheimer's but also play roles in normal physiology, such as pigmentation.
  • Protease activity is crucial for generating amyloidogenic substrates, including amyloid-beta (Aβ) from amyloid precursor protein (APP).
  • Melanocyte Protein (PMEL) processing by proteases is necessary for functional amyloid formation in melanogenesis, but the specific enzymes remain unclear.

Purpose of the Study:

  • To identify the enzyme responsible for processing PMEL during melanogenesis.
  • To elucidate the role of BACE2 in the generation of functional amyloids and pigmentation.

Main Methods:

  • Biochemical and morphological analyses.
  • RNA silencing and pharmacologic inhibition of BACE2.
  • BACE2 overexpression in a human melanocytic cell line.
  • Analysis of coat color defects in Bace2 knockout mice.

Main Results:

  • BACE2, not BACE1, processes PMEL to generate functional amyloids.
  • Bace2 knockout mice exhibit coat color defects, indicating BACE2's role in melanogenesis.
  • BACE2 cleaves PMEL in the juxtamembrane domain, releasing the luminal domain for amyloid fibril formation.
  • BACE2 activity is essential for downstream melanosome morphogenesis.

Conclusions:

  • BACE2 is identified as the enzyme that processes PMEL, generating functional amyloids crucial for pigmentation.
  • This study highlights a significant physiological function for BACE2 in the process of melanogenesis.
  • The findings draw parallels between the generation of PMEL-derived functional amyloids and APP-derived pathological amyloids.

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