Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two fatal neurodegenerative disorders with considerable clinical, pathological and genetic overlap. Both disorders are characterized by the accumulation of pathological protein aggregates that contain a number of proteins, most notably TAR DNA binding protein 43 kDa (TDP-43). Surprisingly, recent clinical studies suggest that dyslipidemia, high body mass index, and type 2 diabetes mellitus are associated with better clinical outcomes in ALS. Moreover, ALS and FTLD patients have a significantly lower incidence of cardiovascular disease, supporting the idea that an unfavorable metabolic profile may be beneficial in ALS and FTLD. The two most widely studied ALS/FTLD models, super-oxide dismutase 1 (SOD1) and TAR DNA binding protein of 43 kDA (TDP-43), reveal metabolic dysfunction and a positive effect of metabolic strategies on disease onset and/or progression. In addition, molecular studies reveal a role for ALS/FTLD-associated proteins in the regulation of cellular and whole-body metabolism. Here, we systematically evaluate these observations and discuss how changes in cellular glucose/lipid metabolism may result in abnormal protein aggregations in ALS and FTLD, which may have important implications for new treatment strategies for ALS/FTLD and possibly other neurodegenerative conditions.

中文翻译：

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ALS / FTLD中代谢紊乱的疾病缓解作用

肌萎缩性侧索硬化症（ALS）和额颞叶变性（FTLD）是两种致命的神经退行性疾病，在临床，病理和遗传学上有相当多的重叠。两种疾病的特征均在于病理蛋白质聚集体的积累，其中所述病理蛋白质聚集体包含许多蛋白质，最显着的是TAR DNA结合蛋白43 kDa（TDP-43）。令人惊讶的是，最近的临床研究表明血脂异常，高体重指数和2型糖尿病与ALS的较好临床结局有关。此外，ALS和FTLD患者的心血管疾病发生率显着降低，支持了不良的代谢状况可能对ALS和FTLD有益的观点。研究最广泛的两个ALS / FTLD模型，即超氧化物歧化酶1（SOD1）和TAR DNA结合蛋白43 kDA（TDP-43），揭示代谢功能障碍和代谢策略对疾病发作和/或进展的积极作用。此外，分子研究揭示了ALS / FTLD相关蛋白在调节细胞和全身代谢中的作用。在这里，我们系统地评估这些观察结果，并讨论细胞葡萄糖/脂质代谢的变化如何导致ALS和FTLD中异常的蛋白质聚集，这可能对ALS / FTLD和其他可能的神经退行性疾病的新治疗策略具有重要意义。