Abstract
Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a polyglutamine-repeat expansion in the huntingtin protein. Activation of the kynurenine pathway of tryptophan degradation is implicated in the pathogenesis of HD. Indoleamine-2,3-dioxygenase (IDO) catalyzes the oxidation of tryptophan to kynurenine, the first step in this pathway. The prevalent, neuroinvasive protozoal pathogen Toxoplasma gondii (T. gondii) results in clinically silent life-long infection in immune-competent individuals. T. gondii infection results in activation of IDO which provides some protection against the parasite by depleting tryptophan which the parasite cannot synthesize. The kynurenine pathway may therefore represent a point of synergism between HD and T. gondii infection. We show here that IDO activity is elevated at least four-fold in frontal cortex and striata of non-infected N171-82Q HD mice at 14-weeks corresponding to early–advanced HD. T. gondii infection at 5 weeks resulted in elevation of cortical IDO activity in HD mice. HD-infected mice died significantly earlier than wild-type infected and HD control mice. Prior to death, infected HD mice demonstrated decreased CD8+ T-lymphocyte proliferation in brain and spleen compared to wild-type infected mice. We demonstrate for the first time that HD mice have an altered response to an infectious agent that is characterized by premature mortality, altered immune responses and early activation of IDO. Findings are relevant to understanding how T. gondii infection may interact with pathways mediating neurodegeneration in HD.
Highlights
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG-repeat expansion in exon-1 of the huntingtin gene (HTT) that results in expression of a polyglutamine-expanded huntingtin protein [1]
Cortical IDO1 mRNA was increased by infection (F(1,14) = 9.06, p = 0.0094); both infected wild-type and HD mice had elevated IDO1 mRNA compared to respective non-infected mice (p = 0.0484 and 0.0123, respectively) (Fig 2B)
We modeled the effect of the prevalent human infection T. gondii in HD mice and are the first to demonstrate that HD mice have an altered response to a live infectious agent
Summary
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG-repeat expansion in exon-1 of the huntingtin gene (HTT) that results in expression of a polyglutamine-expanded huntingtin protein [1]. Mutant huntingtin protein (mhtt) expression results in disruption of many down-stream processes including energy metabolism, gene transcription and immune activation [2,3,4]. While CAG expansion size is the main determinant of age of disease onset there is considerable variation in age of onset after correction for CAG mutation size. This variability is explained in part by as yet unknown environmental modifiers of HD [5]
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