Metabolic Reprogramming in Astrocytes Distinguishes Region-Specific Neuronal Susceptibility in Huntington Mice.

Metabolic Reprogramming in Astrocytes Distinguishes Region-Specific Neuronal Susceptibility in Huntington Mice.

Publication date: Jun 04, 2019

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.

Polyzos, A.A., Lee, D.Y., Datta, R., Hauser, M., Budworth, H., Holt, A., Mihalik, S., Goldschmidt, P., Frankel, K., Trego, K., Bennett, M.J., Vockley, J., Xu, K., Gratton, E., and McMurray, C.T. Metabolic Reprogramming in Astrocytes Distinguishes Region-Specific Neuronal Susceptibility in Huntington Mice. 06517. 2019 Cell Metab (29):6.

Concepts Keywords
Alternative Fuel Gluconeogenesis
Amino Acids Neurodegeneration
Astrocytes Reactive oxygen species
Brain Carcinogenesis
Cerebellum Mitochondrion
Endogenous Central nervous system
Energy Astrocyte
Fatty Acids Metabolism
Gluconeogenesis Senescence
Glucose Branches of biology
Glycolytic Energy cost
Huntington
Mitochondria
Oxygen
Pentose Phosphate Shunt
ROS
Stress
Stress Response
Striatum
Substrate
Toxicity

Semantics

Type Source Name
pathway BSID Metabolism
pathway BSID DNA Repair
pathway BSID Stress response
pathway BSID Gluconeogenesis
drug DRUGBANK Amino acids
gene UNIPROT MAGEE1
gene UNIPROT ROS1
drug DRUGBANK Rosoxacin
pathway BSID Fatty acids
drug DRUGBANK D-glucose
drug DRUGBANK Dextrose unspecified form
disease MESH Huntington disease
disease DOID Huntington disease

Original Article

Leave a Comment

Your email address will not be published. Required fields are marked *