Abstract：
: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.
journal_name
Cell Metabjournal_title
Cell metabolismauthors
Polyzos AA,Lee DY,Datta R,Hauser M,Budworth H,Holt A,Mihalik S,Goldschmidt P,Frankel K,Trego K,Bennett MJ,Vockley J,Xu K,Gratton E,McMurray CTdoi
10.1016/j.cmet.2019.03.004subject
Has Abstractpub_date
2019-06-04 00:00:00pages
1258-1273.e11issue
6eissn
1550-4131issn
1932-7420pii
S1550-4131(19)30132-9journal_volume
29pub_type
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