The DOI matches its Crossref record; 43 of the 43 references it cites were found in a registry or an index.
BACE2 processes PMEL to form the melanosome amyloid matrix in pigment cells
Open accessAbstract
Amyloids are often associated with pathologic processes such as in Alzheimer's disease (AD), but can also underlie physiological processes such as pigmentation. Formation of pathological and functional amyloidogenic substrates can require precursor processing by proteases, as exemplified by the generation of Aβ peptide from amyloid precursor protein (APP) by beta-site APP cleaving enzyme (BACE)1 and γ-secretase. Proteolytic processing of the pigment cell-specific Melanocyte Protein (PMEL) is also required to form functional amyloid fibrils during melanogenesis, but the enzymes involved are incompletely characterized. Here we show that the BACE1 homologue BACE2 processes PMEL to generate functional amyloids. BACE2 is highly expressed in pigment cells and Bace2(-/-) but not Bace1(-/-) mice display coat color defects, implying a specific role for BACE2 during melanogenesis. By using biochemical and morphological analyses, combined with RNA silencing, pharmacologic inhibition, and BACE2 overexpression in a human melanocytic cell line, we show that BACE2 cleaves the integral membrane form of PMEL within the juxtamembrane domain, releasing the PMEL luminal domain into endosomal precursors for the formation of amyloid fibrils and downstream melanosome morphogenesis. These studies identify an amyloidogenic substrate of BACE2, reveal an important physiological role for BACE2 in pigmentation, and highlight analogies in the generation of PMEL-derived functional amyloids and APP-derived pathological amyloids.
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“Pharmacological inhibition of BACE2 results in depigmentation, the most consistent side effect seen in preclinical studies of BACE1/BACE2 inhibition (9).”
From The β-Secretase BACE1 in Alzheimer’s Disease (2021) · cites this paper as [9]
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The β-Secretase BACE1 in Alzheimer’s Disease
Hampel, H., Vassar, R., De Strooper, B., Hardy, J., Willem, M., Singh, N., Zhou, J., Yan, R., Vanmechelen, E., De Vos, A., et al. (2021) · Biological Psychiatry · doi:10.1016/j.biopsych.2020.02.001 · Cited by 694
Targeting the β secretase BACE1 for Alzheimer's disease therapy
Yan, R., & Vassar, R. J. (2014) · The Lancet Neurology · doi:10.1016/s1474-4422(13)70276-x · Cited by 645
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Juan, T., & Fürthauer, M. (2017) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2017.08.022 · Cited by 479
Kennedy, M. E., Stamford, A. W., Chen, X., Cox, K., Cumming, J. N., Dockendorf, M. F., Egan, M. F., Ereshefsky, L., Hodgson, R. A., Hyde, L. A., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aad9704 · Cited by 441
BACE1 inhibitor drugs in clinical trials for Alzheimer’s disease
Vassar, R. J. (2014) · Alzheimer s Research & Therapy · doi:10.1186/s13195-014-0089-7 · Cited by 421
Metadata
- Authors
- Rochin, L., Hurbain, I., Serneels, L., Fort, C., Watt, B., Leblanc, P., Marks, M. S., De Strooper, B., Raposo, G., & van Niel, G.
- Affiliations
- Institut Curie, Centre de Recherche and
- Centre National de la Recherche Scientifique (FR)
- KU Leuven (BE)
- University of Pennsylvania (US)
- École Normale Supérieure de Lyon (FR)
- Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases, University of Leuven, 3000 Leuven, Belgium;
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-06-10
- Volume
- 110
- Issue
- 26
- Pages
- 10658-10663
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3696817
- OpenAlex
- W2074095545
- Cited by
- 186
- References
- 43
- Citations by year
- 2026: 14 · 2025: 16 · 2024: 9 · 2023: 10 · 2022: 6 · 2021: 17 · 2020: 16 · 2019: 15 · 2018: 20 · 2017: 15 · 2016: 24 · 2015: 11 · 2014: 11 · 2013: 1
- FWCI
- 9.28
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Lirias (submittedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-11-LABX-0038)
- National Institutes of Health (5r01ar048155-13)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR-048155)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Keywords
- BACE2, PMEL, melanosomes, amyloid fibrils, melanogenesis, pigment cells, BACE1, amyloid precursor protein, pigmentation
- MeSH terms
- Amyloid, Animals, Cell Line, HeLa Cells, Humans, Melanins, Melanocytes, Mice, Inbred C57BL, Pigment Epithelium of Eye, Protein Processing, Post-Translational, RNA, Messenger, Skin Pigmentation, Aspartic Acid Endopeptidases, Mice, Knockout, Melanosomes, RNA, Small Interfering, Mice, Amyloid Precursor Protein Secretases, gp100 Melanoma Antigen
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