Interfering with aggregated α-synuclein in advanced melanoma leads to a major upregulation of MHC class II proteins

Area of Science:

• Oncology
• Immunology
• Neuroscience

Background:

• Advanced melanoma, a deadly skin cancer, shows increased levels of the intrinsically disordered protein alpha-synuclein (α-synuclein).
• While toxic to neurons in Parkinson's disease, α-synuclein supports melanoma cell proliferation and metastasis.
• Understanding this dual role of α-synuclein is crucial for developing targeted melanoma therapies.

Purpose of the Study:

• To investigate the opposite roles of α-synuclein in advanced melanoma.
• To explore the effects of the small-molecule compound anle138b on α-synuclein in melanoma.
• To identify molecular mechanisms underlying anle138b's impact on melanoma progression and immune response.

Main Methods:

• Proteomic analysis of human melanoma cell lines with high α-synuclein expression treated with anle138b.
• Proteomic and transcriptomic analysis of human melanoma xenografts treated systemically with anle138b.
• Investigated the binding of anle138b to and interference with α-synuclein oligomers.

Main Results:

• Anle138b interferes with the oligomeric structure of α-synuclein.
• Interference with oligomerized α-synuclein led to significant upregulation of major histocompatibility complex (MHC) proteins in melanoma cells.
• Upregulation of MHC proteins is associated with enhanced anti-melanoma immune responses.

Conclusions:

• Targeting α-synuclein oligomers with compounds like anle138b can modulate melanoma cell behavior.
• Disrupting α-synuclein in melanoma promotes an anti-tumor immune response through MHC upregulation.
• Anle138b represents a potential therapeutic strategy for advanced melanoma by leveraging its effects on α-synuclein and the immune system.