Aldehyde adducts inhibit 3,4-dihydroxyphenylacetaldehyde-induced α-synuclein aggregation and toxicity: Implication for Parkinson neuroprotective therapy.

3,4-Dihydroxyphenylacetaldehyde (DOPAL), the monoamine oxidase (MAO) metabolite of dopamine, plays a role in pathogenesis of Parkinson disease, inducing α-synuclein aggregation. DOPAL generates discrete α-synuclein aggregates. Inhibiting this aggregation could provide therapy for slowing Parkinson disease progression. Primary and secondary amines form adducts with aldehydes. Rasagiline and aminoindan contain these amine groups. DOPAL-induced α-synuclein aggregates were resolved in the presence and absence of rasagiline or aminoindan using quantitative Western blotting. DOPAL levels in incubation mixtures, containing increased rasagiline or aminoindan concentrations, were determined by high pressure liquid chromatography (HPLC). Schiff base adducts between DOPAL and rasagiline or aminoindan were determined using mass spectrometry. A neuroprotective effect of rasagiline and aminoindan against DOPAL-induced toxicity was demonstrated using PC-12 cells. Rasagiline and aminoindan significantly reduced aggregation of α-synuclein of all sizes in test tube and PC-12 cells experiments. Dimethylaminoindan did not reduce aggregation. DOPAL levels in incubation mixtures were reduced with increasing rasagiline or aminoindan concentrations but not with dimethylaminoindan. Schiff base adducts between DOPAL and either rasagiline or aminoindan were demonstrated by mass spectrometry. A neuroprotective effect against DOPAL-induced toxicity in PC-12 cells was demonstrated for both rasagiline and aminoindan. Inhibiting DOPAL-induced α-synuclein aggregation through amine adducts provides a therapeutic approach for slowing Parkinson disease progression.