Modeling Parkinson's disease genetics: Altered function of the dopamine system in Adh4 knockout mice

Class IV alcohol dehydrogenase (ADH4) efficiently reduces aldehydes produced during lipid peroxidation, and may thus serve to protect from toxic effects of aldehydes e.g. on neurons. We hypothesized that ADH4 dysfunction may increase risk for Parkinson's disease (PD) and previously reported association of an ADH4 allele with PD. We found that a promoter polymorphism in this allele induced a 25–30% reduction of transcriptional activity. Based on these findings, we have now investigated whether Adh4 homo- (Adh4−/−) or heterozygous (Adh4+/−) knockout mice display any dopamine system-related changes in behavior, biochemical parameters or olfaction compared to wild-type mice. The spontaneous locomotor activity was found to be similar in the three groups, whereas administration of d-amphetamine or apomorphine induced a significant increase in horizontal activity in the Adh4−/− mice compared to wild-type mice. We measured levels of monoamines and their metabolites in striatum, frontal cortex and substantia nigra and found increased levels of dopamine and DOPAC in substantia nigra of Adh4−/− mice. Investigation of olfactory function revealed a reduced sense of smell in Adh4−/− mice accompanied by alterations in dopamine metabolite levels in the olfactory bulb. Taken together, our results suggest that lack of Adh4 gene activity induces changes in the function of the dopamine system, findings which are compatible with a role of loss-of-function mutations in ADH4 as possible risk factors for PD.

Research highlights▶ d-Amphetamine induces increase in horizontal activity in Adh4−/− compared to Adh4+/+. ▶ Apomorphine induces increase in horizontal activity in Adh4−/− compared to Adh4+/+. ▶ Adh4−/− mice have increased levels of dopamine and DOPAC in substantia nigra. ▶ Adh4−/− mice have reduced sense of smell compared to Adh4+/+.