Novel genetic mutation discovered in Parkinson’s disease

Mutations in the human genome may be responsible for many diseases. In the case of Parkinson’s disease (PD), five locations have been the subject of recent attention. Variants of one of these locations, ACMSD (amino-carboxymuconate semialdehyde decarboxylase), may be implicated in PD, but until now, no mutations in ACMSD have been found in any PD patients.

The novel ACMSD mutation was identified during a genetic screening study of 62 PD patients on the Mediterranean island of Menorca, which were matched with 192 ethnicity-matched neurologically normal individuals with no family history of PD.

Genetic variants found in these individuals were checked against various databases to identify normal variations observed in other populations.

While researchers found mutations already associated with PD, they discovered one novel mutation in the ACMSD gene in a single patient with no family history of PD and none of the known PD-related mutations found in other populations.

The ACMSD gene encodes for an enzyme in the kynurenine pathway, amino-carboxymuconate semialdehyde decarboxylase, involved in the metabolism of tryptophan. Some metabolites of the kynurenine pathway are known to play an important role in the central nervous system in both health and disease states.

Specifically, ACMSD activity results in less accumulation of quinolinic acid which is a molecule known to have neurotoxic properties. Not only does quinolinic acid cause excitotoxicity, but it can also directly activate the immune cells of the brain, i.e. microglia, and thereby trigger inflammation. Therefore, there is a good pathobiological rationale for why reduced levels of functional ACMSD can result in the type of neurodegeneration seen in PD brains.