Plasticity of Carbohydrate Transport at the Blood-Brain Barrier

Abstract

Neuronal function is highly energy demanding, requiring efficient transport of nutrients into the central nervous system (CNS). Simultaneously the brain must be protected from the influx of unwanted solutes. Most of the energy is supplied from dietary sugars, delivered from circulation via the blood-brain barrier (BBB). Therefore, selective transporters are required to shuttle metabolites into the nervous system where they can be utilized. The Drosophila BBB is formed by perineural and subperineurial glial cells, which effectively separate the brain from the surrounding hemolymph, maintaining a constant microenvironment. We identified two previously unknown BBB transporters, MFS3 (Major Facilitator Superfamily Transporter 3), located in the perineurial glial cells, and Pippin, found in both the perineurial and subperineurial glial cells. Both transporters facilitate uptake of circulating trehalose and glucose into the BBB-forming glial cells. RNA interference-mediated knockdown of these transporters leads to pupal lethality. However, null mutants reach adulthood, although they do show reduced lifespan and activity. Here, we report that both carbohydrate transport efficiency and resulting lethality found upon loss of MFS3 or Pippin are rescued via compensatory upregulation of Tret1-1, another BBB carbohydrate transporter, in Mfs3 and pippin null mutants, while RNAi-mediated knockdown is not compensated for. This means that the compensatory mechanisms in place upon mRNA degradation following RNA interference can be vastly different from those resulting from a null mutation.

A natural genetic variation screen identifies insulin signaling, neuronal communication, and innate immunity as modifiers of hyperglycemia in the absence of Sirt1

“…The copyright holder for this preprint this version posted September 14, 2021. ; https://doi.org/10.1101/2021.09.13.460173 doi: bioRxiv preprint Genes involved in central glucose metabolism as well as insulin signaling are also candidate modifiers. MFS5 acts as a transporter of both glucose and trehalose for the uptake of these sugars from circulation (McMullen et al 2021). Glucose-6-phosphatase (G6P) is the last ratelimiting step in both gluconeogenesis and glycogenolysis, which are used to generate glucose for release into the body during fasting (Gaudet et al 2011;Lizák et al 2019).…”

Redundant functions of the SLC5A transporters Rumpel, Bumpel, and Kumpel in ensheathing glial cells

“…In addition, MFS3 and Pippin are involved in carbohydrate transport in the perineurial glia. Interestingly, MFS3 or Pippin null mutants are rescued via compensatory upregulation of Tret1-1, another bloodbrain barrier carbohydrate transporter, while RNAi-mediated knockdown of Mfs3 and pippin is not compensated for (McMullen et al, 2020). Trehalose is subsequently metabolically Biology Open • Accepted manuscript processed through glycolysis.…”

“…In Drosophila the blood-brain barrier is established by perineurial and subperineurial glial cells ( Stork et al, 2008 ). Perineurial cells express trehalose transporters and participate in maintaining the energy homeostasis of the brain ( McMullen et al, 2020 ; Volkenhoff et al, 2015 ). The subperineurial glial cells block paracellular diffusion by interdigitating cell–cell processes and the formation of septate junctions ( Babatz et al, 2018 ; Bundgaard and Abbott, 2008 ; Schwabe et al, 2005 ; Stork et al, 2008 ).…”

Multifunctional Targeting Liposomes of Epirubicin Plus Resveratrol Improved Therapeutic Effect on Brain Gliomas

“…However, the MAN-modified liposome, the same as glucose, would be pumped out to bloodstream after entering CNS, thus preventing the concentration of chemotherapeutic agent in the brain because of the GLUT1 expressing on both the luminal and abluminal membranes on the endothelial cells of BBB. 19 This indicated that other ways are needed to enhance the ability to cross the BBB and increase drug concentration in the brain.…”