Abstract
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.
Highlights
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that is characterized by the progressive degeneration of both upper and lower motor neurons, which results in a multitude of motor symptoms, including muscle weakness, fasciculations, spasticity, dysphagia, and eventually respiratory dysfunction [167]
Both wild-type TAR DNA binding protein 43 kDa (TDP-43) and fused in sarcoma (FUS) regulate the expression of anti-oxidative genes, and their loss of function may lead to increased cell toxicity by reactive oxygen species (ROS) [115, 154]
Conclusions and future directions In conclusion, the current clinical literature suggests that metabolic factors, such as body mass index (BMI), diet and exercise, and metabolic disorders, such as Type 2 diabetes mellitus (DM) (T2DM) and dyslipidemia, have a disease-modifying effect in ALS and potentially in frontotemporal lobar degeneration (FTLD) (Table 1)
Summary
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that is characterized by the progressive degeneration of both upper and lower motor neurons, which results in a multitude of motor symptoms, including muscle weakness, fasciculations, spasticity, dysphagia, and eventually respiratory dysfunction [167]. TARDBP regulates glycolysis in a hepatocellular carcinoma cell line through the miRNA-mediated posttranscriptional regulation of a key rate-limiting glycolytic enzyme phosphofructokinase (PFKP) [131] These studies highlight an important role for TDP-43 in the regulation of key metabolic processes, including glucose and lipid transport and metabolism, and provide a basis for the observed disease-modifying effect of metabolic dysfunction in ALS and FTLD. High levels of glucose and/or lipids may counteract the cellular toxicity that arises from abnormal protein aggregation in ALS/FTLD neurons Both wild-type TDP-43 and FUS regulate the expression of anti-oxidative genes, and their loss of function may lead to increased cell toxicity by reactive oxygen species (ROS) [115, 154]. While obesity in mid-life is associated with an increased risk of AD [85, 184], a higher BMI later in life, and slower BMI decline after onset of AD and slow disease progression [71]
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