Is the Enzyme ACMSD a Novel Therapeutic Target in Parkinson's Disease?

Abstract

Several large genome wide association studies have identified a locus in close proximity to the gene encoding the enzyme aminocarboxymuconate-semialdehyde-decarboxylase (ACMSD) to be associated with the risk for Parkinson's disease (PD), tentatively suggesting that this enzyme might influence PD pathogenesis. Further support for this comes from the recent identification of a disease-segregating stop codon mutation in ACMSD in a family with Parkinsonism, and a missense mutation in the ACMSD gene predicted to disrupt enzyme function in an individual with typical PD. ACMSD is part of the kynurenine pathway, responsible for the catalytic breakdown of tryptophan into NAD+, generating several neuroactive metabolites in the process. The enzyme is located at a key branch-point of the pathway, limiting the production of the neurotoxin quinolinic acid, which has excitotoxic and inflammatory properties. In this review, we discuss the genetic findings in light of the functions of ACMSD and its potential involvement in PD pathogenesis.

Keywords: ACMSD; Parkinson’s disease; excitotoxicity; kynurenine pathway; neuroinflammation; oxidative stress.

Fig.1

Gene regulatory effects of a PD-associated SNP near the ACMSD gene. The SNP rs6430538, located upstream of the ACMSD gene, was significantly associated with PD in two large GWAS meta-analyses [14, 15]. Eight SNPs (rs10928512, rs1942041, rs6741007, rs6751833, rs6753334, rs4953936, rs6759811, rs6758044) were found to be in linkage-disequilibrium (LD) with rs6430538, as determined by the rAggr program (http://raggr.usc.edu) with an R²≥0.8. The – Log₁₀(P-value) represents the significance of each SNP in the LD block, as reported [15]. The LD block containing the PD-associated rs6430538 SNP exhibits 17 chromatin interactions, as identified by Hi-C analysis reported on the 4DGenome (https://4dgenome.research.chop.edu). Chromatin states in the adult brain substantia nigra (blue) and fetal brain (pink) tissue were determined by the NIH Epigenomics Roadmap.

Fig.2

Simplified diagram of the enzymes and metabolites of the kynurenine pathway. IDO, indoleamine-2,3-dioxygenase; TDO, tryptophan-2,3-dioxygenase; KATs, kynurenine aminotransferases; KMO, kynurenine-3-monooxygenase; 3-HAO, 3-hydro-xyanthranilate-3,4-dioxygenase; ACMSD, aminocarboxymuconate-semialdehyde decarboxylase; QPRT, quinolinate phosphoribosyltransferase; NAD, nicotinamide adenine dinucleotide.

Fig.3

A. Schematic diagram depicting the interrelationships between putative triggers of Parkinson’s disease (PD) and three pathogenetic mechanism that are believed to contribute to the development of neuropathology. We suggest that these events are enhanced by aging. In this model, we propose that ACMSD activity can reduce the likelihood that potential disease triggers actually lead to PD. B. Physiological state.

Fig.4

Schematic diagram describing a model for possible interactions between quinolinic acid and different cell types in the brain, when it comes to pathogenetic mechanisms that are highly relevant to Parkinson’s disease. In this model, we propose that a relative lack of ACMSD increases the levels of quinolinic acid and consequently elevates the risk for excitotoxicity and neuroinflammation. Maroon arrows depict an increase activity of a molecular pathway, and the green T-bar illustrates inhibition.