Examining the degree of neuroprotective effects of ACMSD in the AAV-α-synuclein Parkinson’s Disease animal model

Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by impaired motor function including tremor, rigidity, akinesia and postural instability as well as non-motor symptoms including cognitive impairment, depression, and anxiety. Pathological indices of PD consist of protein aggregation of α-synuclein (ɑ-syn), striatal dopaminergic denervation and the loss of dopaminergic neurons in the substantia nigra. While the exact causes of PD remain unknown, substantial evidence suggests that the kynurenine pathway (KP), a pathway upregulated in response to inflammation, is implicated in its pathology. Under normal physiological conditions, the KP catabolizes the amino acid tryptophan to the metabolite 2-amino-3-carboxymuconate-6-semialdehyde (ACMS). ACMS is then spontaneously converted to quinolinic acid (QA), which is an intermediate in the formation of nicotinamide adenine dinucleotide (NAD+), a cofactor in mitochondrial respiration, thus serving as an essential molecule in cellular energy metabolism. QA itself may serve as a contributing factor in PD pathology as this metabolite promotes oxidative stress, mitochondrial dysfunction, excitotoxicity, and positively correlates with increased scores in the Unified Parkinson’s Disease Rating Scale (UPDRS) in motor experiences of daily living (UPDRS II) and motor complications (UPDRS III). ACMS is enzymatically converted to picolinic acid (PA), an iron chelator and anti-viral agent, by 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase (ACMSD), thus limiting the formation of QA and potentially conferring neuroprotective effects. To model Parkinson’s disease, we overexpressed α-synuclein unilaterally in the substantia nigra with an adeno-associated virus (AAV), which leads to dose-dependent neurodegeneration, aggregation of α-syn and motor impairments. This model may therefore serve to examine perturbations of the KP in the context of PD including increased QA/PA expression. We hypothesize that the overexpression of the enzyme ACMSD in the AAV-α-syn model of PD will reduce the degree of neurodegeneration and inflammation and prevent motor decline. Neurodegeneration and neuroinflammation will be quantified histologically, through stereology and densitometry respectively. Observable PD-like symptoms will be quantified using behavioral assessments, particularly the cylinder test and amphetamine induced rotations to assess the degree of motor decline.