UV-induced prion-like aggregate seeding of melanosomal proteins is a driver of chronic dyspigmentation

Summary: Abstract Body: Cutaneous hyperpigmentation due to triggers such as UV, inflammation, or hormones represents a clinical challenge disproportionally affecting women and people of color. Chronic cases often show melanized dermal deposits which histiocytes, here termed melanophages, are slow to remove for unclear reasons. Interestingly, melanosomes physiologically organize melanin around insoluble PMEL amyloid fibrils which show prion-like self-aggregatory activity. Our work also confirms that alpha-synuclein (aSyn), a component of Lewy body amyloid in Parkinson’s disease, is expressed in melanocytes as an MITF target. Using primary human cells and a new aSyn overexpression mouse model, we demonstrate that ROS from sources such as UV exacerbates pathologic aggregation of melanin together with these inherently amyloidogenic proteins, with the skin of these mice developing striking dark macules and dermal melanophage accumulation after exposure. We also use the Real-Time Quaking-Induced Conversion Assay to show that UV increases aSyn and PMEL’s prion-like self-aggregation capacity in human skin explants. In parallel we demonstrate that these proteins, upregulated with tanning, are concurrently removed via autophagy activation by MITF, suggesting pigmentation-induced aggregatory toxicity is a routine stress which melanocytes have evolved specific homeostatic mechanisms to manage. For validation, we show that biopsies of hyperpigmentation disorders are enriched in aSyn and PMEL amyloid extracellularly and within melanophages. RNAseq data also suggest that aggregation can trigger cellular senescence, offering a possible explanation for the common clinical co-occurrence of hyper- and hypopigmentation. Ultimately, our data indicate that hyperpigmentation in some ways represents a form of proteinopathy similar to Alzheimer’s or Parkinson’s disease, suggesting that dissolution of protein aggregates may represent a new strategy to treat chronic dyschromia of multiple etiologies. Nicholas Theodosakis¹, Stephen Ostrowski¹, Thomas Horn¹, Michael Marks², David Fisher¹ 1. Dermatology, Massachusetts General Hospital, Boston, MA, United States. 2. Pathology, The Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, United States. Pigmentation, Melanoma, and Melanoma Immune Surveillance