Of mice, rats and men: Revisiting the quinolinic acid hypothesis of Huntington's disease

Abstract

The neurodegenerative disease Huntington's disease (HD) is caused by an expanded polyglutamine (polyQ) tract in the protein huntingtin (htt). Although the gene encoding htt was identified and cloned more than 15 years ago, and in spite of impressive efforts to unravel the mechanism(s) by which mutant htt induces nerve cell death, these studies have so far not led to a good understanding of pathophysiology or an effective therapy. Set against a historical background, we review data supporting the idea that metabolites of the kynurenine pathway (KP) of tryptophan degradation provide a critical link between mutant htt and the pathophysiology of HD. New studies in HD brain and genetic model organisms suggest that the disease may in fact be causally related to early abnormalities in KP metabolism, favoring the formation of two neurotoxic metabolites, 3-hydroxykynurenine and quinolinic acid, over the related neuroprotective agent kynurenic acid. These findings not only link the excitotoxic hypothesis of HD pathology to an impairment of the KP but also define new drug targets and therefore have direct therapeutic implications. Thus, pharmacological normalization of the imbalance in brain KP metabolism may provide clinical benefits, which could be especially effective in early stages of the disease.

Figure 1

Schematic representation of the “axon-sparing”, excitotoxic nerve cell loss in the HD neostriatum. Degenerated neurons in this simplistic model are indicated by dotted lines.

Figure 2

Rotational behavior in rodents with unilateral striatal excitotoxic lesions. Degenerated neurons are indicated by dotted lines. The arrow indicates the rotational direction following the systemic administration of a dopamine receptor agonist.

Figure 3

Chemical structures of kainic, ibotenic, glutamic and quinolinic acids.

Figure 4

Anti-excitotoxic neuroprotection: effects of an intrahippocampal ibotenate injection (5 μg) in the absence (a) or presence (b) of D-amino-phosphonoheptanoic acid (5 μg) in rats. Arrowheads demarcate the tracks of the injection needles. Bar: 500 μM. (From Schwarcz et al., 1982).

Figure 5

The kynurenine pathway of tryptophan degradation in mammalian cells.

Figure 6

Schematic representation of non-cell-autonomous neurodegeneration in HD. (From Guidetti et al., 2006).