Metabolic Reprogramming in Astrocytes Distinguishes Region-Specific Neuronal Susceptibility in Huntington Mice, 2019, McMurray et al

Andy · Aug 11, 2019

Highlights

Region-specific neuronal toxicity arises from metabolic reprogramming in astrocytes

Glucose is low in the Huntington striatum but neuronal mitochondria are unaffected

Astrocytes compensate by fuel switching to fatty acids but increase oxygen damage

Toxicity occurs when oxygen damage exceeds the energy benefits of fatty acid oxidation

Summary
The basis for region-specific neuronal toxicity in Huntington disease is unknown. Here, we show that region-specific neuronal vulnerability is a substrate-driven response in astrocytes. Glucose is low in HdhQ( 150/150) animals, and astrocytes in each brain region adapt by metabolically reprogramming their mitochondria to use endogenous, non-glycolytic metabolites as an alternative fuel. Each region is characterized by distinct metabolic pools, and astrocytes adapt accordingly. The vulnerable striatum is enriched in fatty acids, and mitochondria reprogram by oxidizing them as an energy source but at the cost of escalating reactive oxygen species (ROS)-induced damage. The cerebellum is replete with amino acids, which are precursors for glucose regeneration through the pentose phosphate shunt or gluconeogenesis pathways. ROS is not elevated, and this region sustains little damage. While mhtt expression imposes disease stress throughout the brain, sensitivity or resistance arises from an adaptive stress response, which is inherently region specific. Metabolic reprogramming may have relevance to other diseases.
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Paywall, https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30132-9
Sci hub, https://sci-hub.se/10.1016/j.cmet.2019.03.004

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Metabolic Reprogramming in Astrocytes Distinguishes Region-Specific Neuronal Susceptibility in Huntington Mice, 2019, McMurray et al

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Metabolic Reprogramming in Astrocytes Distinguishes Region-Specific Neuronal Susceptibility in Huntington Mice, 2019, McMurray et al

Andy Committee Member

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