Cited by 313Tryptophan and brain disordersNeuroinflammation and Neurodegeneration MechanismsAmino Acid Enzymes and Metabolism

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The kynurenine pathway and neurodegenerative disease

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Maddison, Daniel C., Giorgini, Flaviano·2015·Seminars in Cell & Developmental Biology

DOI 10.1016/j.semcdb.2015.03.002

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Abstract

Neuroactive metabolites of the kynurenine pathway (KP) of tryptophan degradation have been closely linked to the pathogenesis of several neurodegenerative diseases. Tryptophan is an essential amino acid required for protein synthesis, and in higher eukaryotes is also converted into the key neurotransmitters serotonin and tryptamine. However, in mammals >95% of tryptophan is metabolized through the KP, ultimately leading to the production of nicotinamide adenosine dinucleotide (NAD(+)). A number of the pathway metabolites are neuroactive; e.g. can modulate activity of several glutamate receptors and generate/scavenge free radicals. Imbalances in absolute and relative levels of KP metabolites have been strongly associated with neurodegenerative disorders including Huntington's, Alzheimer's, and Parkinson's diseases. The KP has also been implicated in the pathogenesis of other brain disorders (e.g. schizophrenia, bipolar disorder), as well as several cancers and autoimmune disorders such as HIV. Pharmacological and genetic manipulation of the KP has been shown to ameliorate neurodegenerative phenotypes in a number of model organisms, suggesting that it could prove to be a viable target for the treatment of such diseases. Here, we provide an overview of the KP, its role in neurodegeneration and the current strategies for therapeutic targeting of the pathway.

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Authors: Maddison, D. C., & Giorgini, F.
Affiliations: University of Leicester (GB)
Corresponding author: Giorgini, Flaviano
ORCID: Maddison, Daniel C.
Giorgini, Flaviano
Venue: Seminars in Cell & Developmental Biology
Publisher: Elsevier BV
Published: 2015-04
Volume: 40
Pages: 134-141
ISSN: 1084-9521 (ISSN-L)
DOI: 10.1016/j.semcdb.2015.03.002
OpenAlex: W1990201789
Cited by: 309
References: 94
Citations by year: 2026: 17 · 2025: 31 · 2024: 29 · 2023: 30 · 2022: 32 · 2021: 47 · 2020: 33 · 2019: 27 · 2018: 19 · 2017: 21 · 2016: 17 · 2015: 6
FWCI: 1.20
Type: journal article
Language: en
Open access: green
figshare.com
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Seminars in Cell and Developmental Biology (publishedVersion)
PubMed (publishedVersion)
Figshare (submittedVersion, cc-by)
ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
Leicester Research Archive (University of Leicester) (submittedVersion, other-oa)
Funders: the Midlands Integrative Biosciences Training Partnership (MIBTP)
the Biotechnology and Biological Sciences Research Council (BBSRC)
the Medical Research Council (MRC)
the CHDI Foundation
Topics: Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Keywords: kynurenine pathway, tryptophan metabolism, neurodegenerative diseases, NAD biosynthesis, kynurenine metabolites, glutamate receptors, free radicals, Huntington's disease, Alzheimer's disease, Parkinson's disease, schizophrenia, bipolar disorder, HIV, therapeutic targeting, neuroactive metabolites
MeSH terms: Animals, Humans, Kynurenine, Tryptophan, Neurodegenerative Diseases, Metabolic Networks and Pathways

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The kynurenine pathway and neurodegenerative disease

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