Researchers from the University of New York in Buffalo observed significant barrier deficiency in a novel model of frataxin-deficient human brain microvascular endothelial cells (hBMVECs). The molecular alterations identified in the study are suggestive of increased barrier permeability and paracellular solute flux in Friedreich ataxia (FA).

“Our data provide a new understanding of [blood-brain barrier] function in [FA], identifying a potential therapeutic target in the neuroinflammation, neurodegeneration, brain iron accumulation, and stroke in this disease,” the authors said in the study, which is in preprint and has not been peer-reviewed.

The researchers found lower levels of polymerized total actin and peripheral actin in frataxin-deficient hBMVECs than in control cells. Frataxin-deficient hBMVECs showed a nearly 20% reduction in filamentous actin (F-actin). This decrease in F-actin was particularly evident at the cell membrane and cortical actin ring and suggested alterations in cytoskeleton architecture.

Accordingly, frataxin-deficient hBMVECs showed increased paracellular permeability, as demonstrated by the increased flux of a cell-impermeant fluorescent tracer across the frataxin-deficient barrier compared to control conditions. Moreover, the analysis of transendothelial electrical resistance revealed a clear deficit in the barrier integrity of frataxin-deficient hBMVECs compared to that of control cells at all time points.

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The researchers used a lentivirus-mediated short hairpin RNA to generate the frataxin-deficient hBMVEC model. The model retained important features of FA, including increased oxidative stress and decreased oxidative energy metabolism and adenosine triphosphate (ATP) production with a shift to glycolysis—2 recognized hallmarks of frataxin loss.

Moreover, frataxin-deficient hBMVECs had a higher number of mitochondria and larger cell size than control cells. The increase in the number of mitochondria seems to be consistent with previous observations suggesting aberrant mitochondrial dynamics in both fission and fusion pathways in FA.


Smith FM, Kosman DJ. Frataxin-deficient human brain microvascular endothelial cells lose polymerized actin and are paracellularly permeable–implications for blood-brain barrier integrity in Friedreich’s ataxia. bioRxiv. Published online February 10, 2023. doi:10.1101/2023.02.09.527936