Abstract Details

FXTAS is caused by premutations of the fragile X mental retardation 1 (FMR1) gene with 55-200 CGG repeats. Premutation carriers are at increased risk of developing intention tremor, ataxia, parkinsonism, and cognitive impairment with age. Mitochondrial dysfunction contributes to FXTAS pathogenesis.

The objective of this study was to develop biomarkers reflecting mitochondrial dysfunction in fragile X-associated tremor/ataxia syndrome (FXTAS) using plasma neuron-derived extracellular vesicles (NDEVs) from living patients and controls, and assess their biological validity in frozen brain tissues.

We isolated plasma NDEVs by immunoaffinity capture targeting L1CAM from 8 FXTAS patients (stage 1-4) and 4 male controls and measured the quantity and activity of complex IV and V (also termed ATP synthase). Additionally, we processed frozen cerebellar and frontal cortex samples from a separate cohort of 8 FXTAS patients (stage 4-5) and 9 male controls and evaluated the same measures.

In NDEVs, FXTAS patients compared to controls had lower activity of complex IV (0.027 vs. 0.046 AU, p = 0.02) and ATP synthase (0.037 vs. 0.062 AU, p = 0.046), but also higher ATP synthase quantity (0.0024 vs. 0.0016 AU, p = 0.03). ATP synthase activity was negatively correlated with FXTAS stage (r = -0.613, p = 0.045). The cerebellum of FXTAS patients compared to controls had lower complex IV quantity (2.004 vs 9.226 AU, p = 0.005) and activity (0.191 vs. 0.604 AU, p = 0.01); and lower ATP synthase quantity (7.852 vs. 19.953 AU, p = 0.037). No differences were observed for frontal cortex.

Quantitative and functional abnormalities in mitochondrial electron transport chain and ATP production are manifest in plasma NDEVs of FXTAS patients and correlate with disease severity. These abnormalities may be predominantly attributable to the cerebellum. Plasma NDEVs may provide biomarkers for FXTAS prediction and monitoring.