Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Tel Aviv 6997801, Israel.
Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada V5A 1S6.
Open Biol. 2018 Jan;8(1). doi: 10.1098/rsob.170229.
The accumulation of various metabolites appears to be associated with diverse human diseases. However, the aetiological link between metabolic alteration and the observed diseases is still elusive. This includes the correlation between the abnormally high levels of homocysteine and quinolinic acid in Alzheimer's disease, as well as the accumulation of oncometabolites in malignant processes. Here, we suggest and discuss a possible mechanistic insight into metabolite accumulation in conditions such as neurodegenerative diseases and cancer. Our hypothesis is based on the demonstrated ability of metabolites to form amyloid-like structures in inborn error of metabolism disorders and the potential of such metabolite amyloids to promote protein aggregation. This notion can provide a new paradigm for neurodegeneration and cancer, as both conditions were linked to loss of function due to protein aggregation. Similar to the well-established observation of amyloid formation in many degenerative disorders, the formation of amyloids by tumour-suppressor proteins, including p53, was demonstrated in malignant states. Moreover, this new paradigm could fill the gap in understanding the high occurrence of specific types of cancer among genetic error of metabolism patients. This hypothesis offers a fresh view on the aetiology of some of the most abundant human maladies and may redirect the efforts towards new therapeutic developments.
各种代谢物的积累似乎与多种人类疾病有关。然而，代谢改变与观察到的疾病之间的病因联系仍然难以捉摸。这包括阿尔茨海默病中同型半胱氨酸和喹啉酸水平异常升高，以及恶性肿瘤过程中癌代谢物的积累之间的相关性。在这里，我们提出并讨论了一种可能的机制见解，即代谢物在神经退行性疾病和癌症等情况下的积累。我们的假设基于代谢性疾病中代谢物形成淀粉样结构的能力，以及这种代谢物淀粉样物促进蛋白质聚集的潜力。这一概念为神经退行性疾病和癌症提供了一个新的范例，因为这两种疾病都与蛋白质聚集导致的功能丧失有关。类似于许多退行性疾病中淀粉样形成的既定观察结果，在恶性状态下也证明了肿瘤抑制蛋白（包括 p53）的淀粉样形成。此外，这一新范例可以填补代谢遗传错误患者中特定类型癌症高发的理解空白。这一假说为一些最常见的人类疾病的病因提供了新的视角，并可能促使人们努力开发新的治疗方法。
