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Rapid Generation of Amyloid from Native Proteins In vitro
Published on: December 5, 2013
UV induces common cutaneous amyloid-like melanosomal protein aggregates
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.
Insights
Melanosomal proteinopathy, involving alpha-synuclein aggregates, contributes to skin hyperpigmentation and aging. UV light worsens this, but melanocytes use autophagy to clear aggregates, a key tanning function.
Area of Science:
- Dermatology
- Molecular Biology
- Neuroscience
Background:
- Proteinopathies, like Parkinson's disease, involve protein misfolding and aggregation.
- Alpha-synuclein is implicated in neurodegenerative proteinopathies.
- Melanosomal protein PMEL forms physiologic scaffolds but can ectopically accumulate in skin hyperpigmentation.
Purpose of the Study:
- To investigate the role of melanocytic alpha-synuclein and protein aggregation in cutaneous pigmentary disorders.
- To explore the mechanisms of protein aggregate formation and clearance in melanocytes.
- To identify potential therapeutic targets for melanocyte dysfunction.
Main Methods:
- Molecular, proteomic, and electron microscopic analyses of clinical samples and cell/mouse models.
- Real Time Quaking-Induced Conversion Assay (RT-QuIC) to assess protein self-propagation.
- CUT&RUN chromatin profiling and single-cell RNA-seq to study gene regulation and cellular processes.
Main Results:
- Melanocytic alpha-synuclein forms intracellular aggregates similar to those in Parkinson's disease and extracellular deposits in hyperpigmentation.
- UV radiation induces self-propagation of misfolded melanosomal proteins in a prion-like manner.
- Melanocytes use MITF-regulated autophagy to remove aggregates, identifying aggregate clearance as a core tanning function.
- Impaired intracellular aggregate removal leads to melanocyte senescence, exacerbating hypopigmentation and photoaging.
Conclusions:
- Melanosomal proteinopathy is a common factor in melanocyte dysfunction and pigmentary disorders.
- Aggregate removal is a critical function of melanocytes, particularly during tanning.
- Targeting protein aggregate management offers a potential therapeutic strategy for melanocyte dysfunction and related skin conditions.
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