Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA.
Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA.
Genes Dev. 2018 Nov 1;32(21-22):1380-1397. doi: 10.1101/gad.315564.118. Epub 2018 Oct 26.
Cells undergo metabolic adaptation during environmental changes by using evolutionarily conserved stress response programs. This metabolic homeostasis is exquisitely regulated, and its imbalance could underlie human pathological conditions. We report here that C9orf72, which is linked to the most common forms of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), is a key regulator of lipid metabolism under stress. Loss of C9orf72 leads to an overactivation of starvation-induced lipid metabolism that is mediated by dysregulated autophagic digestion of lipids and increased de novo fatty acid synthesis. C9orf72 acts by promoting the lysosomal degradation of coactivator-associated arginine methyltransferase 1 (CARM1), which in turn regulates autophagy-lysosomal functions and lipid metabolism. In ALS/FTD patient-derived neurons or tissues, a reduction in C9orf72 function is associated with dysregulation in the levels of CARM1, fatty acids, and NADPH oxidase NOX2. These results reveal a C9orf72-CARM1 axis in the control of stress-induced lipid metabolism and implicates epigenetic dysregulation in relevant human diseases.
细胞在环境变化时通过利用进化保守的应激反应程序来进行代谢适应。这种代谢平衡受到精细调控，其失衡可能是人类病理状况的基础。我们在这里报告，与最常见的神经退行性疾病肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）相关的 C9orf72 是应激下脂质代谢的关键调节剂。C9orf72 的缺失导致饥饿诱导的脂质代谢过度激活，其机制是通过自噬性消化脂质的失调和新脂肪酸合成的增加介导的。C9orf72 通过促进共激活因子相关精氨酸甲基转移酶 1（CARM1）的溶酶体降解来发挥作用，从而调节自噬溶酶体功能和脂质代谢。在 ALS/FTD 患者来源的神经元或组织中，C9orf72 功能的降低与 CARM1、脂肪酸和 NADPH 氧化酶 NOX2 的水平失调有关。这些结果揭示了 C9orf72-CARM1 轴在应激诱导的脂质代谢中的控制作用，并暗示了表观遗传失调与相关人类疾病有关。
