Although the exact causes of PD remain unknown, it is likely a combination of several factors. Many interrelated hypotheses have been postulated about the death of dopaminergic neurons including genetic defects, environmental toxins, inflammation, deficiencies in the mitochondrial respiratory chain, and reduced capacity of transmitters, including monoamine storage vesicles and glutamate metabolism. However, no experimental animal models testing these hypotheses show all the features characterizing PD. Moreover, most animal models of PD use exogenous toxins to kill dopaminergic neurons in the SN, which may not relate to cases of idiopathic PD in humans. The involvement of DA or one of its metabolites also may be important in the death of DA SN neurons. The “catecholaldehyde hypothesis” of PD proposes that an accumulation of a toxic intermediate of dopamine metabolism, 3,4dihydroxyphenylacetaldehyde, is toxic to nigral neurons and leads to PD. DOPAL is the catabolic product of dopamine via oxidative deamination by monoamine oxidase, and is quickly cleaved by aldehyde dehydrogenase into 3,4dihydroxyphenylacetic acid. DOPAL is an endogenous toxin found in dopaminergic cells in human SN and could contribute to the development of PD. Here we examine whether DOPAL WZ4002 selectively kills dopaminergic neurons in the SN. Our laboratories have shown that DA itself is not sufficiently toxic at physiological levels to induce either neuronal death or aggregation of a-synuclein, thus implicating a metabolite of DA. Investigations in several laboratories have implicated a metabolite of DA as an endogenous toxin which triggers DA neuron loss. DOPAL levels of 2–3 mM are normally present in SN from neurologically intact human patients at autopsy. However, DOPAL levels increase in the SN and striatum in PD while ALDH1A1 mRNA, protein and activity decrease in the SN and striatum, implicating DOPAL as a potential endogenous toxin. Moreover, we have shown that DOPAL is toxic to neurons at physiological concentrations in vitro and also triggers aggregation of asynuclein. Earlier experiments provided immunohistochemical evidence of DOPAL toxicity in vivo by showing loss of tyrosine hydroxylase immunoreactivity after DOPAL injections into rat SN. However these studies did not exclude the possibility that DOPAL injections may have decreased tyrosine hydroxylase synthesis and protein levels resulting in decreased THir as was shown for DA. Here we determined that DOPAL induces loss of striatal DA in vivo using tyrosine hydroxylase immunohistochemistry and show that DOPAL is toxic to DA neurons in vivo with definitive neuronal counts using unbiased stereology. In addition we show that DOPAL injections into SN produce a behavioral model of PD. The experiments provided herein strongly reinforce the notion that DOPAL is an endogenous neurotoxin, and implicate it as the trigger which kills dopaminergic neurons in the SN and leads to Parkinson disease.