Abstract
It is important to understand how the disease process affects the metabolic pathways in amyotrophic lateral sclerosis and whether these pathways can be manipulated to ameliorate disease progression. To analyse the basis of the metabolic defect in amyotrophic lateral sclerosis we used a phenotypic metabolic profiling approach. Using fibroblasts and reprogrammed induced astrocytes from C9orf72 and sporadic amyotrophic lateral sclerosis cases we measured the production rate of reduced nicotinamide adenine dinucleotides (NADH) from 91 potential energy substrates simultaneously. Our screening approach identified that C9orf72 and sporadic amyotrophic lateral sclerosis induced astrocytes have distinct metabolic profiles compared to controls and displayed a loss of metabolic flexibility that was not observed in fibroblast models. This loss of metabolic flexibility, involving defects in adenosine, fructose and glycogen metabolism, as well as disruptions in the membrane transport of mitochondrial specific energy substrates, contributed to increased starvation induced toxicity in C9orf72 induced astrocytes. A reduction in glycogen metabolism was attributed to loss of glycogen phosphorylase and phosphoglucomutase at the protein level in both C9orf72 induced astrocytes and induced neurons. In addition, we found alterations in the levels of fructose metabolism enzymes and a reduction in the methylglyoxal removal enzyme GLO1 in both C9orf72 and sporadic models of disease. Our data show that metabolic flexibility is important in the CNS in times of bioenergetic stress.
Highlights
Amyotrophic lateral sclerosis (ALS) is an incurable adult onset disease with a lifetime risk of 1 in 400
This principal component analysis (PCA) analysis indicated that our phenotypic screening approach could be used to identify distinct metabolic profiles in fibroblasts and induced astrocytes isolated from C9orf72 and sporadic ALS (SALS) cases as observed previously using classical metabolomic approaches (Rozen et al, 2005; Blasco et al, 2010, 2014, 2017; Kumar et al, 2010)
No loss of metabolic flexibility was observed in C9orf72 or SALS fibroblasts compared to controls (Supplementary Fig. 3B and C)
Summary
Amyotrophic lateral sclerosis (ALS) is an incurable adult onset disease with a lifetime risk of 1 in 400. Given that clinical evidence supports a negative impact of dysfunctional energy metabolism on the disease progression in ALS (Desport et al, 2005; Dupuis et al, 2011), it is vital to understand how ALS affects astrocyte metabolic processes including metabolic flexibility (the ability of a cell to mobilize and use alternative substrates to meet energy demands) This understanding would offer the potential for the pathways in question to be manipulated with strategies to improve bioenergetic output and increase the metabolic support for motor neurons. Using both patient derived fibroblasts and reprogrammed human induced astrocytes, we used a phenotypic metabolic profiling approach (Bochner et al, 2011; Boccuto et al, 2013) to identify deficient metabolic pathways This technology enables the comparison of normal versus disease model cells by simultaneously comparing the rates of energy production from 91 potential energy substrates. We present for the first time alterations in glycogen metabolism, fructose metabolism, methylglyoxal detoxification and mitochondrial substrate transport, which all could contribute to a loss of metabolic flexibility in C9orf astrocytes, making them vulnerable to starvation-induced cell stress under times of bioenergetic deficit
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
