Indoleamine 2,3-dioxygenase as a novel therapeutic target for Huntington’s disease

ABSTRACT

Introduction: Huntington’s disease (HD) is an autosomal dominant, neurodegenerative disorder. Despite the severe motor, psychiatric and cognitive symptoms and the great socioeconomic burden caused by the disease, available treatment is mainly symptomatic.

The kynurenine pathway (KP) is the main metabolic route of tryptophan degradation, in the course of which several neuroactive compounds are generated. The imbalance of the neurotoxic and neuroprotectant metabolites can lead to excitotoxicity and overproduction of reactive oxygen species, which both contribute to the progression of HD. Indoleamine 2,3-dioxygenase 1 (IDO1) is a key enzyme of the KP that has various immune modulatory roles.

Areas covered: Current knowledge of the involvement of KP in HD pathogenesis with a particular focus on IDO1. By reviewing the diverse roles of the enzyme in kynurenine production, immune modulation, and serotonin metabolism, we elucidate the factors that make this enzyme a therapeutic target.

Expert opinion: Due to the complexity of HD and the various effects that IDO1 exerts, targeting this enzyme, while highly profitable, may be a great challenge. Through IDO1 activity, neurodegeneration, inflammatory processes and depressive symptoms, often related to HD, can be modulated. Ongoing trials of IDO1 inhibitors in other areas of medicine offer advantages for initiating approaches toward this enzyme as a therapeutic target.

Trial registration: ClinicalTrials.gov identifier: NCT02855476.

Trial registration: ClinicalTrials.gov identifier: NCT02519036.

KEYWORDS:

• Huntington’s disease
• kynurenine pathway
• indoleamine 2
• 3-dioxygenase
• IDO1
• excitotoxicity
• inflammation
• depression

Article highlights

• A growing body of evidence supports the involvement of the KP in HD pathogenesis.

• The upregulated state of the pathway results in the excessive production of neurotoxic metabolites such as QUIN and 3-HK and a decrease in the level of the neuroprotective KYNA.

• IDO1 catalyzes the first step of the KP and has various roles in modulating immune responses.

• Inhibition of the first step of the KP was proven to be neuroprotective, as it shifted the pathway toward the formation of KYNA and reduced QUIN-induced toxicity by decreasing the levels of 3-HK.

• Adjusting IDO1 activity could be beneficial in HD therapy as it would restore the balance between neuroprotective and neurotoxic kynurenine compounds, modulate the upregulated inflammatory state and alleviate depressive symptoms often present with the disease.

• Testing IDO1 inhibitor compounds that have been proven to be safe in other areas of medicine could be a cost and time effective way of trying novel therapeutic agents for HD.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded. The current work was supported by Economic Development and Innovation Operational Programme - GINOP-2.3.2-15-2016-00034, Hungarian Brain Research Program − Grant No. 2017-1.2.1-NKP-2017-00002 NAP VI/4, Ministry of Human Capacities, Hungary grant 20391-3/2018/FEKUSTRAT and the MTA-SZTE Neuroscience Research Group of the Hungarian Academy of Sciences and the University of Szeged.