Parkinson's disease and a dopamine-derived neurotoxin, 3,4-Dihydroxyphenylacetaldehyde : implications for proteins, microglia, and neurons

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder for which the greatest risk factor is age. Four to five percent of 85-year-olds suffer from this debilitating disease, which is characterized by the selective loss of dopaminergic neurons within the substantia nigra and the presence of protein aggregates known as Lewy bodies. While the etiology of this disease is still unknown, recent research implicates oxidative stress, activated microglia, and reactive dopamine (DA) metabolites to play a role in the initiation or progression of the disease. Activated microglia cause injury to dopaminergic neurons via a host of mechanisms, including reactive oxygen species production, release of cytokines, and phagocytic activity. Microglial activation has been detected in the brains of PD patients, but the source of this activation has not been elucidated. Previous research has shown electrophiles and endogenous neurotoxins to play a role in this microglial activation. The interaction between the neurotoxic metabolite of DA, 3,4dihydroxyphenylacetaldehyde (DOPAL), and microglia has not been explored. DOPAL is a highly reactive, bifunctional electrophile produced by oxidative deamination of DA by monoamine oxidase (MAO). DOPAL is oxidized in the major metabolism pathway to 3,4-dihydroxyphenylacetic acid (DOPAC) by aldehyde dehydrogenase (ALDH). DOPAL has previously been shown to be 100-fold more toxic than DA in vitro and in vivo. Potent inhibition of the rate-limiting enzyme in DA biosynthesis, tyrosine hydroxylase, by DOPAL has been well-established. DOPALmediated aggregation of α-synuclein, the primary component of PD-hallmark Lewy bodies, has been suggested but was further explored in this work.