[Seminar] The kynurenine pathway and neurodegeneration: mechanisms and therapeutic targets

Seminar

Title: The kynurenine pathway and neurodegeneration: mechanisms and therapeutic targets

Speaker: Flaviano Giorgini

Affiliation: Department of Genetics, University of Leicester

Host: Federico Herrera, Cell Structure and Dynamics Lab

Abstract:

The kynurenine pathway (KP), the major mode of tryptophan degradation in mammals, has been implicated in the pathophysiology of several neurodegenerative disorders, including Huntington’s disease (HD), Alzheimer’s disease (AD), and Parkinson’s disease (PD). The KP was first implicated in these diseases approximately 30 years ago when it was found that intrastriatal injection of the KP metabolite quinolinic acid (QUIN) reproduces many hallmarks of HD in rodents. It has since been found that the KP contains other neuroactive metabolites: the neurotoxin 3‐hydroxykynurenine (3‐HK) and the neuroprotectant kynurenic acid (KYNA). Much work has shown that perturbation of KP metabolism is a hallmark of HD pathology, and that changes in brain levels of KP metabolites may play a causative role in this disease via a combination of excitotoxic mechanisms and oxidative stress. Though less studied, similar KP perturbations been noted in other neurodegenerative diseases.

The KP enzyme kynurenine 3‐monooxygenase (KMO) emerged as a promising therapeutic target for HD from a genome‐wide screen we conducted in yeast. KMO is located at a critical branching point in the KP such that inhibition of this enzyme by either pharmacological or genetic means shifts the flux in the pathway towards the formation of KYNA. Our recent work in Drosophila models of HD, AD, and PD has found that inhibition of KMO increases levels of KYNA relative to 3‐HK and ameliorates neurodegeneration, as well as other disease-relevant phenotypes in these models. Furthermore, feeding of KP metabolites to flies directly modulates neurodegeneration, underscoring the causative nature of these metabolites. In combination with recent promising work in mouse models of neurodegeneration, it is clear that perturbations of the KP observed in brain diseases play an important role in pathology, and that pharmacological interrogation of this pathway will likely play an important therapeutic role in these disorders.

Speaker's short biography:

Flaviano Giorgini is a native of Indiana, and obtained his bachelor’s degree in biological sciences from Purdue University in 1992. He subsequently performed master’s degree studies at Washington University in Saint Louis and doctoral as well as postdoctoral research at the University of Washington. In 2006 he established his research group at the University of Leicester (UK), and has been recently promoted to the position of Professor of Neurogenetics. His research is focused on identifying genetic modifiers of Huntington’s and Parkinson’s diseases, with the goal of developing novel therapeutic approaches for these devastating disorders and better understanding their underlying pathologies. This research has investigated several promising therapeutic targets for neurodegenerative disease, such as KMO (Giorgini et al., Nat Genet, 2005; Campesan et al., Curr Biol, 2011; Zwilling et al., Cell, 2011; Amaral et al., Nature, 2013; Giorgini et al., J Biol Chem, 2013); glutathione peroxidase activity (Mason et al., Nat Genet, 2013); and Rab11 (Richards et al., Cell Death Differ, 2011; Steinhert et al., Hum Mol Genet 2012; Breda et al., Hum Mol Genet, 2014). In addition, his work has led to novel insights into the function of the protein DJ-1, mutations in which cause a hereditary form of Parkinson’s (Repici et al., J Mol Med, 2013; Sajjad et al., Hum Mol Genet, 2014; Miller-Fleming et al., PNAS, 2014; Zondler et al., Cell Death Dis, 2014).