Impaired aldehyde detoxification exacerbates motor deficits in an alpha-synuclein mouse model of Parkinson's disease

IntroductionThe discovery of biogenic aldehydes in the postmortem parkinsonian brain and the ability of these aldehydes to modify and cross-link proteins has called attention to their possible role in Parkinson's disease. For example, many in vitro studies have found that the aldehyde metabolite of dopamine, 3,4-dihydroxyphenylacetaldehyde (DOPAL), induces the formation of stable, neurotoxic alpha-synuclein oligomers. MethodsTo study this in vivo, mice deficient in the two aldehyde dehydrogenase enzymes (Aldh1a1 and Aldh2, DKO) primarily responsible for detoxification of DOPAL in the nigrostriatal pathway were crossed with mice that overexpress human wild-type alpha-synuclein. DKO overexpressing human wild-type alpha-synuclein (DKO/ASO) offspring were evaluated for impairment on motor tasks associated with Parkinsonism. ResultsDKO/ASO mice developed severe motor deficits greater than that of mice overexpressing human wild-type alpha-synuclein alone. ConclusionThese results provide evidence to support the idea that biogenic aldehydes such as DOPAL interact with human wild-type alpha-synuclein, directly or indirectly, in vivo to exacerbate locomotor deficits in Parkinson's disease.

Automated summary

The presence of biogenic aldehydes in the brain of postmortem Parkinson's disease patients and their ability to modify proteins and cause cross-linking has raised the possibility of their involvement in the disease. In this study, mice lacking the two aldehyde dehydrogenase enzymes responsible for detoxifying one of these aldehydes were crossed with mice that overexpress human alpha-synuclein, a protein associated with Parkinson's disease. The results showed that the combination of the aldehyde deficiency and alpha-synuclein overexpression resulted in more severe motor deficits than either factor alone.