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Metabolic signatures of amyotrophic lateral sclerosis reveal insights into disease pathogenesis

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Metabolic dysfunction is an important modulator of disease course in amyotrophic lateral sclerosis (ALS). We report here that a familial mouse model (transgenic mice over-expressing the G93A mutation of the Cu/Zn superoxide dismutase 1 gene) of ALS enters a progressive state of acidosis that is associated with several metabolic (hormonal) alternations that favor lipolysis. Extensive investigation of the major determinants of H(+) concentration (i.e., the strong ion difference and the strong ion gap) suggests that acidosis is also due in part to the presence of an unknown anion. Consistent with a compensatory response to avert pathological acidosis, ALS mice harbor increased accumulation of glycogen in CNS and visceral tissues. The altered glycogen is associated with fluctuations in lysosomal and neutral α-glucosidase activities. Disease-related changes in glycogen, glucose, and α-glucosidase activity are also found in spinal cord tissue samples of autopsied patients with ALS. Collectively, these data provide insights into the pathogenesis of ALS as well as potential targets for drug development.
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... In disease, TDP-43 accumulates in the cytoplasm of cells in pathological aggregates that can disrupt normal cellular functions and promote chronic stress (46,47). Abnormal accumulation of TDP-43 also leads to disruption in metabolic pathways such as glucose, lipid, and mitochondrial metabolism (31,(50)(51)(52). These metabolic changes further contribute to pathological progression and disrupt energy states needed for normal function and stress resolution in neurons (50)(51)(52)(53). ...
... Abnormal accumulation of TDP-43 also leads to disruption in metabolic pathways such as glucose, lipid, and mitochondrial metabolism (31,(50)(51)(52). These metabolic changes further contribute to pathological progression and disrupt energy states needed for normal function and stress resolution in neurons (50)(51)(52)(53). ...
... This impairment persists throughout the course of disease and is due to altered levels of phosphorylase B or the enzyme that degrades glycogen (53). Similar results were found in spinal cord tissue of patients with ALS, confirming that glycogen accumulation is a feature of the human disease (52). In our study, we observed elevated levels of glycogen in the brains of TDP-43-expressing flies, indicating disrupted glycogen storage and metabolism in these animals. ...
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... Consistent with our findings, increased glycogen storage in the central nervous system has been observed in ALS patients and ALS animal models [72]. Furthermore, some FDG-PET studies in ALS patients have linked reduced glucose uptake and phosphorylation with disease severity and early diagnosis of ALS [73,74]. ...
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... This theoretical proprioceptive Piezo2 channelopathy-derived hippocampal metabolic alteration may eventually lead to a more widespread metabolic dysfunction that propels the ALS disease course. This may include progressive acidosis, glycogen accumulation, and lipolysis [83]. It is notable that voluntary exercise enhances spatial memory [84] and this finding is in support of the theory that Piezo2-induced enhanced resonance initiates the synchronization of the theta rhythm ON by providing the spatial input into the hippocampal theta rhythm [19]. ...
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... Transcription and splicing of nuclear-encoded mitochondrial protein genes similar changes in substrate uptake and use 65,129,130,161,162 and changes in mitochondrial function 151,161,[163][164][165][166] are becoming well understood. Regarding the clinical relevance of these findings, the breadth of mitochondrial alterations that are proposed to lead to bioenergetic failure in preclinical models have also been consistently observed in the brain, spinal cord and skeletal muscle of people living with ALS 163,[167][168][169][170][171][172][173][174][175][176][177][178][179][180] . ...
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