PgmNr D206: Inhibiting lipid transfer between neurons and glia by modulating lactate levels delays neurodegeneration.

Authors:
Lucy Liu 1 ; Hugo Bellen 1,2


Institutes
1) Baylor College of Medicine, Houston, TX; 2) Howard Hughes Medical Institute, Houston, TX.


Keyword: neural degeneration

Abstract:

High levels of Reactive oxygen species (ROS) and the presence of mitochondrial defects in neurons are implicated in neurodegeneration. Previously, we have shown that lipid droplets (LD) accumulate in glia prior to neurodegeneration due to high levels of ROS activating neuronal C-Jun N-terminal Kinase (JNK) and Sterol Regulatory Element Binding Protein (SREBP). Activating lipogenesis in neurons alone will cause glial LD accumulation, suggesting that lipids are transferred from neurons to glia. However, the mechanism by which these lipids transfer is unexplored. Through a candidate gene screen designed to isolate genes involved in lipid transfer, we isolated monocarboxylate transporters (MCTs) along with fatty acid transporters and apolipoproteins, all of which are critical for eventual lipid transfer and glial LD accumulation. Furthermore, we have established a potential mechanism by which the lipids are transferred from the neuron to the glia. The pathway starts with the observation that glial cells secrete lactate via MCTS. This lactate is taken up by the neuronal MCTs. The neuron converts lactate to pyruvate to be used as an energy source in the TCA cycle. However, in the disease state, excess energy is diverted into the lipid synthesis pathway and lipogenesis is upregulated due to elevated SREBP and Acetyl coA carboxylase (ACC). The lipids are then transfer from the neuron via fatty acid transport protein (FATP) and carried by extracellular apolipoproteins to the glia. Importantly, blocking lactate transfer either genetically or pharmacologically will inhibit glial LD accumulation and delays cell death in mutant flies and in a murine neuronal-glial co-culture model. Similarly, removing FATP or the apolipoproteins also reduces LD accumulation. In brief, we are unraveling a mechanism that leads to lipid production, lipid transfer and lipid accumulation in the nervous system that has not yet been documented and that promotes neurodegeneration.



Flybase Genetic Index:
1. FlyBase gene symbol: SREBP; FBgn: FBgn0261283
2. FlyBase gene symbol: bsk; FBgn: FBgn0000229
3. FlyBase gene symbol: Fatp; FBgn: FBgn0267828
4. FlyBase gene symbol: Sln; FBgn: FBgn0033657
5. FlyBase gene symbol: Glaz; FBgn: FBgn0033799