A number of genetic studies have linked variation in the enzyme aminocarboxy-muconate semialdehyde decarboxylase (ACMSD) with a risk for Parkinson’s disease (PD), such that increased levels of ACMSD are associated with a reduced risk for PD while mutations in the enzyme result in parkinsonian deficits. ACMSD generates picolinic acid, a neuroprotective compound, at the expense of quinolinic acid, a neurotoxic substrate thought to play a role in PD; an increase in its activity should therefore be neuroprotective. Our work shows that increasing ACMSD in the brain protects dopaminergic neurons in a toxin-induced pre-clinical model, justifying further testing to validate ACMSD as a therapeutic target for PD.
We predict that increasing ACMSD expression in the brain should reduce quinolinic acid levels and increase picolinic acid production, resulting in a dual neuroprotective role that can be assessed in pre-clinical models.
We will increase ACMSD expression in a pre-clinical lipopolysaccharide (toxin-induced), LPS, model of PD to determine if ACMSD can reduce neurodegeneration and associated behavioral deficits. We will selectively target either neurons or microglia (the immune cells in the brain) to determine if increased ACMSD in either cell population mitigates nigral neurodegeneration. We predict that ACMSD overexpression will lead to better survival of dopaminergic neurons and enhanced performance in behavioral tests.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Demosntrating that ACMSD overexpression reduces inflammation and improves dopaminergic neuronal survival is the first prerequisite for the development of novel therapies targeting ACMSD and aimed at slowing PD progression.
Next Steps for Development:
Once we determine the effects of increasing ACMSD activity on this model of localized neuroinflammation, we can launch a program to further validate ACMSD as a PD therapeutic target in additional pre-clinical PD models.