Age‐dependent alterations of the kynurenine pathway in the YAC128 mouse model of Huntington disease. (15th July 2013)

• Record Type: Journal Article
• Authors: Mazarei, Gelareh; Budac, David P.; Lu, Ge; Adomat, Hans; Tomlinson Guns, Emma S.; Möller, Thomas; Leavitt, Blair R.
• Is Part Of: Journal of neurochemistry. Volume 127:Number 6(2013:Dec.)
• Page Start: 852
• Page End: 867
• Publication Date: 2013-07-15
• Subjects: Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.12350
• Languages: English
• ISSNs: 0022-3042

Abstract

<abstract abstract-type="main" id="jnc12350-abs-0001"> <title>Abstract</title> <p>Indoleamine 2, 3 dioxygenase (<italic>Ido1</italic>), the first and rate‐limiting enzyme of the kynurenine pathway (KP), is a striatally enriched gene with increased expression levels in the YAC128 mouse model of Huntington disease (HD). Our objective in this study was to delineate age‐related KP alterations in this model. Three enzymes potentially catalyze the first step of the KP; <italic>Ido1</italic> and Indoleamine 2, 3 dioxygenase‐2 were highly expressed in the striatum and Tryptophan 2, 3 dioxygenase (<italic>Tdo2</italic>) in the cerebellum. During development, <italic>Ido1</italic> mRNA expression is dynamically regulated and chronically up‐regulated in YAC128 mice. Kynurenine (Kyn) to tryptophan (Trp) ratio, a measure of activity in the first step of the KP, was elevated in YAC128 striatum, but no change in <italic>Tdo2</italic> mRNA levels or Kyn to Trp ratio was detected in the cerebellum. Ido1 induction was coincident with Trp depletion at 3 months and Kyn accumulation at 12 months of age in striatum. Changes in downstream KP metabolites of YAC128 mice generally followed a biphasic pattern with neurotoxic metabolites reduced at 3 months and increased at 12 months of age. Striatally specific induction of <italic>Ido1</italic> and downstream KP alterations suggest involvement in HD pathogenesis, and should be taken into account in future therapeutic developments for HD.</p> </abstract>