Warburg effect linked to cognitive‐executive deficits inFMR1premutation

Abstract

A 55-200 CGG repeat expansion in the 5'-UTR of the fragile X mental retardation 1 (FMR1) gene is known as a premutation. Some carriers are affected by the neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS), primary ovarian insufficiency, and neurobehavioral impairments. Based on the mitochondrial dysfunction observed in fibroblasts and brain samples from carriers, as well as in neurons and brains from a mouse model of the premutation, we evaluated the presence of the Warburg effect in peripheral blood mononuclear cells (PBMCs) from 30 premutation carriers with either a rebalance of the metabolism [increasing glycolysis while decreasing oxidative phosphorylation (oxphos)] or a metabolic amplification (increasing glycolysis while maintaining/increasing oxphos). Deficits in oxphos-more pronounced in FXTAS-affected subjects-were accompanied by a shift toward glycolysis, suggesting increased glycolysis despite aerobic conditions. Differential proteomics extended these findings, unveiling a decreased antioxidant response, translation, and disrupted extracellular matrix and cytoskeleton organization with activation of prosenescence pathways. Lower bioenergetics segregated with increased incidence of low executive function, tremors, below-average IQ, and FXTAS. The combination of functional and proteomic data unveiled new mechanisms related to energy production in the premutation, showing the potential of being applicable to other psychiatric disorders to identify endophenotype-specific responses relevant to neurobiology.-Napoli, E., Song, G., Schneider, A., Hagerman, R., Eldeeb, M. A. A. A., Azarang, A., Tassone, F., Giulivi, C. Warburg effect linked to cognitive-executive deficits in FMR1 premutation.

Plasma Biomarkers for Monitoring Brain Pathophysiology in FMR1 Premutation Carriers

“…Plasma samples were isolated from a single blood draw per individual as previously described ( Napoli et al, 2016b ) Samples were extracted and analyzed by mass spectrometry as described in detail elsewhere ( Napoli et al, 2015 ). Briefly, 30-μl aliquots were extracted by 1 ml of degassed acetonitrile:isopropanol:water (3:3:2, V/V/V) at -20°C, centrifuged and decanted with subsequent evaporation of the solvent to complete dryness.…”

Placebo Response in Fragile X‐associated Tremor/Ataxia Syndrome

“…A maximum score of 27 is possible . A score of ≤14 has been used as cutoff for impairment in FXTAS . The study's secondary outcomes included 3 other cognitive tests (Controlled Oral Word Association Test [COWAT], California Verbal Learning Test [CVLT], and the Weschler Memory Scale [WMS]) as well as 2 other tremor measures (postural tremor severity and writing tremor severity) and 2 bradykinesia measures (hand‐tapping and finger‐tapping frequencies).…”

Metabolic Alterations in FMR1 Premutation Carriers

“…In another study, peripheral blood mononuclear cells (PBMCs) were used to investigate mitochondrial energyproviding systems, and a dynamic alteration of glycolysis was observed when comparing controls, FXTAS-free carriers and FXTAS-affected carriers (Napoli et al, 2016). Specifically, FXTASfree carriers exhibited a comparable or higher abundance of glycolytic proteins (e.g., hexokinase, phosphofructokinase, and pyruvate kinase) than controls, indicating an up-regulation of glycolysis (Napoli et al, 2016).…”