Arnold Moriah R, Chen Suzie, Unni Vivek K
Medical Scientist Training Program, Oregon Health and Science University, Portland, OR, United States.
Department of Neurology and Jungers Center for Neurosciences Research, Oregon Health and Science University, Portland, OR, United States.
Front Oncol. 2025 Mar 20;15:1554059. doi: 10.3389/fonc.2025.1554059. eCollection 2025.
Strong evidence suggests links between Parkinson's Disease (PD) and melanoma, as studies have found that people with PD are at an increased risk of developing melanoma and those with melanoma are at increased risk of developing PD. Although these clinical associations are well-established, the cellular and molecular pathways linking these diseases are poorly understood. Recent studies have found a previously unrecognized role for the neurodegeneration-associated protein alpha-synuclein (αSyn) in melanoma; the overexpression of αSyn promotes melanoma cell proliferation and metastasis. However, to our knowledge, no studies have investigated the role of αSyn in melanoma models outside of a xenograft paradigm.
Our study created and characterized Snca knockout in the spontaneously developing melanoma TG3 mouse line, TG3+/+-/-.
We show that αSyn loss-of-function significantly delays melanoma onset and slows tumor growth in males. Furthermore, decreased tumor volume is correlated with a decreased DNA damage signature and increased apoptotic markers, indicating a role for αSyn in modulating the DNA damage response (DDR) pathway.
Overall, our study may suggest that targeting αSyn and its role in modulating the DDR and melanomagenesis could serve as a promising new therapeutic target.
有力证据表明帕金森病（PD）与黑色素瘤之间存在联系，因为研究发现帕金森病患者患黑色素瘤的风险增加，而黑色素瘤患者患帕金森病的风险也增加。尽管这些临床关联已得到充分证实，但连接这些疾病的细胞和分子途径仍知之甚少。最近的研究发现，神经退行性疾病相关蛋白α-突触核蛋白（αSyn）在黑色素瘤中具有以前未被认识到的作用；αSyn的过表达促进黑色素瘤细胞的增殖和转移。然而，据我们所知，尚无研究在异种移植模式之外的黑色素瘤模型中研究αSyn的作用。
我们的研究在自发发生黑色素瘤的TG3小鼠品系TG3+/+-/-中创建并鉴定了Snca基因敲除。
我们发现，αSyn功能丧失显著延迟了雄性小鼠黑色素瘤的发病并减缓了肿瘤生长。此外，肿瘤体积减小与DNA损伤信号降低和凋亡标志物增加相关，表明αSyn在调节DNA损伤反应（DDR）途径中起作用。
总体而言，我们的研究可能表明，靶向αSyn及其在调节DDR和黑色素瘤发生中的作用可能成为一个有前景的新治疗靶点。
