UV induces common cutaneous amyloid-like melanosomal protein aggregates

Misfolding of aggregation-prone proteins underpins diseases known as proteinopathies. One of these proteins, alpha-synuclein, is a component of aggregates in neurodegenerative conditions such as Parkinson's disease. The melanosomal protein PMEL, which forms physiologic amyloid scaffold structures on which melanin is organized in melanosomes, similarly ectopically accumulates in the dermis in many forms of cutaneous hyperpigmentation. Here, we demonstrate in a wide range of common clinical pigmentary disorders, as well as in primary melanocyte and mouse models examined by molecular, proteomic, and electron microscopic tools, that melanocytic alpha-synuclein is a prominent component of intracellular protein aggregates bound to similar proteins as in Parkinson's disease, as well as melanized extracellular protein deposits. Using the Real Time Quaking-Induced Conversion Assay (RT-QuIC), we demonstrate that UV induces misfolded melanosomal proteins to self-propagate, augmenting this pathology in prion-like fashion. CUT&RUN chromatin profiling and single-cell RNA-seq demonstrate that melanocytes utilize microphthalmia-associated transcription factor (MITF)-regulated autophagy to counteract protein aggregation, identifying aggregate removal as a core function of tanning. In contrast to extracellular aggregation, impaired intracellular aggregate removal contributes to melanocyte senescence, which conversely exacerbates chronic hypopigmentation and photoaging-related discoloration. These findings identify melanosomal proteinopathy as a common contributor to melanocyte dysfunction and suggest aggregate-focused management approaches.

Authors

Institutions

Publication Details

Journal
bioRxiv (Cold Spring Harbor Laboratory)
Published
2025-12-18
DOI
https://doi.org/10.64898/2025.12.17.689083
Primary Topic
melanin and skin pigmentation
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

UV induces common cutaneous amyloid-like melanosomal protein aggregates

Stephen M. Ostrowski, Philip Seifert, William M. Lin, Konrad Kaminiów et al.
bioRxiv (Cold Spring Harbor Laboratory)
melanin and skin pigmentation
article

UV induces common cutaneous amyloid-like melanosomal protein aggregates

Stephen M. Ostrowski, Philip Seifert, William M. Lin, Konrad Kaminiów, Gëorge F. Murphy, Rachit Bakshi, Nicholas Theodosakis, Mai P. Hoang, Aline Fassini, Namrata D. Udeshi, Andrew M. Mu, Kristin C. Shaw, Steven A. Carr, Y.D. Zhang, Nir Hacohen, Khanh Hung Nguyen, Sreeganga S. Chandra, Miroslav Hejna, Sharon Germana, Bradley T. Hyman, Jun S. Song, Remi Joseph, Andrea Ballabio, Xunwei Wu, Anand K. Ganesan, David E. Fisher, Helen Ji, T. Horn, Mariam Y. Demian, Alin Asim, Porter B. Howland, Talya A. Cohen-Neamie, Allison E. Greuel, Judth R. Boozer
article en

Abstract

Misfolding of aggregation-prone proteins underpins diseases known as proteinopathies. One of these proteins, alpha-synuclein, is a component of aggregates in neurodegenerative conditions such as Parkinson's disease. The melanosomal protein PMEL, which forms physiologic amyloid scaffold structures on which melanin is organized in melanosomes, similarly ectopically accumulates in the dermis in many forms of cutaneous hyperpigmentation. Here, we demonstrate in a wide range of common clinical pigmentary disorders, as well as in primary melanocyte and mouse models examined by molecular, proteomic, and electron microscopic tools, that melanocytic alpha-synuclein is a prominent component of intracellular protein aggregates bound to similar proteins as in Parkinson's disease, as well as melanized extracellular protein deposits. Using the Real Time Quaking-Induced Conversion Assay (RT-QuIC), we demonstrate that UV induces misfolded melanosomal proteins to self-propagate, augmenting this pathology in prion-like fashion. CUT&RUN chromatin profiling and single-cell RNA-seq demonstrate that melanocytes utilize microphthalmia-associated transcription factor (MITF)-regulated autophagy to counteract protein aggregation, identifying aggregate removal as a core function of tanning. In contrast to extracellular aggregation, impaired intracellular aggregate removal contributes to melanocyte senescence, which conversely exacerbates chronic hypopigmentation and photoaging-related discoloration. These findings identify melanosomal proteinopathy as a common contributor to melanocyte dysfunction and suggest aggregate-focused management approaches.

bioRxiv (Cold Spring Harbor Laboratory)
Broad Institute (US), Boston University (US), Brigham and Women's Hospital (US), Massachusetts Eye and Ear Infirmary (US), Harvard University (US), University of Illinois Urbana-Champaign (US), Baylor College of Medicine (US), University of California, Irvine (US), Harvard University Press (US), Portland VA Medical Center (US), Yale University (US), Massachusetts General Hospital (US)
Openalex Percentile: Top 57%
melanin and skin pigmentation
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.