Protein adduction by multiple aldehydes contributes to α-synuclein aggregation and dopaminergic neuron loss in rat models of Parkinson's disease

Dopaminergic neurodegeneration in the substantia nigra causes the motor symptoms of Parkinson’s disease (PD). The mechanisms underlying this neurodegeneration remain unclear. Aldehydes exhibit high reactivity that can covalently modify functional proteins and cause cell damage. This study aimed to characterize protein adduction by endogenous aldehydes and investigate its role in dopaminergic neuron loss in PD. Forty free aldehydes were identified in rat models of PD induced by 6-hydroxydopamine (6-OHDA) and rotenone using chemical isotope labeling coupled with high-resolution mass spectrometry. Twenty-two aldehydes were found in the rat brain for the first time. In addition to lipid peroxidation, amine oxidation was the major source of aldehydes. Levels of 27 aldehyde-protein adducts in the substantia nigra and striatum were increased by 1- to 5-fold at 4–6 h after 6-OHDA injection. Consistently, most of these protein adducts were significantly increased in the rotenone model. Application of the trapping reagent phenelzine and the aldehyde dehydrogenase-2 activator Alda-1 reduced protein adduction by aldehydes and attenuated neuron loss induced by 6-OHDA injection. Twelve aldehydes covalently modified α-synuclein in 6-OHDA-treated rats, with the lysine residue in the GLSK peptide identified as the primary binding target. Aldehydes caused peptide crosslinking and aggregation of α-synuclein. Additive effects of covalent modification by aldehydes contributed to neuron death. Collectively, protein adduction by multiple aldehydes contributes to α-synuclein aggregation and dopaminergic neuron loss in rat models of PD. Multiple biogenic aldehydes, especially those from abnormal oxidation of amines, represent a novel class of toxic molecules that play a pathogenic role in PD.