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.

Rare copy number variation in extremely impulsively violent males

“…The other 26 identified clinically relevant CNVs were private. The 19q11‐19q12 duplication, 16p12.1 microdeletion, microdeletions of DLG2 and ARID1B and microduplications of MTOR, ACMSD, MDGA2 and ZFYVE27 were present in individuals who also reported history of criminal conviction in their relatives, further supporting their either firmly established or highly suspected clinical relevance. For the remaining 18 clinically relevant CNVs, the criminal history of siblings was either not mentioned or denied.…”

Kynurenine pathway in Parkinson's disease—An update

“…The expression of allele-specific differences in ACMSD has to be examined to understand an exact link between ACMSD and PD [ 83 ]. From genome-wide association studies, SNPs on ACMSD identified its ability as a risk in PD [ [84] , [85] , [86] , [87] , [88] , [89] , [90] , [91] ]. In a Spanish family, it was found that the family had a history of parkinsonism, epilepsy and myoclonic tremor and also showed mutation in p.Trp26 which is a top codon in ACMSD [ 92 ].…”

“…of exons rs number No. of patients Mutation Results Reference KMO chr 1 17 exons rs2275163 105 cases No association of SNPs First investigation in KMO gene and the genetic link in PD is missing [ 15 ] rs1053230 rs2050518 rs6661244 ACMSD chr 2 13 exons rs6430538 989 PD cases NIL No polymorphism contribute to PD [ 84 ] 599 PD cases T/C No significant difference observed between allelic and genotypic frequencies [ 85 ] 6476 PD cases T/C GWAS studies identified protein altering variants in 29 PD loci. [ 91 ] Case study p.Glu298Lys First study to identify the mutation and this would deregulate kynurenine pathway in some PD cases [ 93 ] 240 T/C GWAS studies analyzed for homozygosity and structural genomic variations which resulted in novel characterization in PD [ 89 ] 13,708 cases T/C Meta-analysis identified the replication association analysis.…”

An Expanded Neuroimmunomodulation Axis: sCD83-Indoleamine 2,3-Dioxygenase—Kynurenine Pathway and Updates of Kynurenine Pathway in Neurologic Diseases

“…PD is normally identified by motor symptoms (bradykinesia, rigidity, resting tremor, and gait disturbances), which are believed to be largely related to the loss of nigral dopamine neurons. Moreover, patients also frequently exhibit a range of non-motor disturbances including constipation, hyposmia, depression, and cognitive decline ( 167 ), being more debilitating than motor signs and worsening with disease progression ( 168 ).…”

“…The enzyme aminocarboxymuconate-semialdehyde-decarboxylase (ACMSD) located at a key branch-point of the KP, limited the production of the neurotoxin QUIN with inflammatory properties. The missense mutation in the ACMSD gene predicted to disrupt enzyme function in typical PD individual, suggesting that this enzyme might influence PD pathogenesis ( 167 ). Vilas et al reported a novel ACMSD mutation resulting in the change of p.Glu298Lys amino-acid in a sporadic PD patient, which was not present in neurologically normal population, suggesting that not only common genetic variability but also rare variants in ACMSD alone might increase the risk of PD ( 182 ).…”