We obtained evidence that inherited synucleinopathy, from mutation of the gene encoding alpha-synuclein or from triplication of the normal gene, results not only in familial parkinsonism but also in cardiac sympathetic denervation. Our neuroimaging findings have been confirmed by post-mortem pathology demonstrating markedly decreased tyrosine hydroxylase immunoreactivity in epicardial nerves from patients with synuclein gene duplication. Based on studies of alpha-synuclein and tyrosine hydroxylase immunoreactivity in cardiac nerves in incidental Lewy body disease (thought to represent pre-symptomatic PD), there appears to be a centripetal, retrograde denervation process, beginning with alpha-synuclein deposition and loss of tyrosine hydroxylase-containing nerves in distal myocardium, followed by more proximal lesions and formation of Lewy bodies in sympathetic ganglia. Eventually, in clinically overt PD, there is no detectable alpha-synuclein deposition in the heart, presumably because of absence of noradrenergic nerves, and the main pathologic findings are absence of epicardial neural tyrosine hydroxylase and presence of ganglionic Lewy bodies. Consistent with a centripetal, retrograde process, follow-up neuroimaging studies have shown early, progressive loss of 6-18Ffluorodopamine-derived radioactivity in the apex and inferolateral walls of the left ventricle, with later loss of more proximal anterobasal septal radioactivity. To understand better the link between alpha-synucleinopathy and catecholaminergic denervation, we are testing hypotheses derived from the concept that cytoplasmic amines are autotoxins. Whereas other groups are focusing on auto-oxidation of cytoplasmic amines, we are focusing on enzymatic autotoxicity. According to the catecholaldehyde hypothesis, cytoplasmic dopamine is converted by mitochondrial monoamine oxidase to the toxic catecholaldehyde, dihydroxyphenylacetaldehyde (DOPAL). DOPAL is detoxified by aldehyde dehydrogenase (ALDH), to form dihydroxyphenylacetic acid (DOPAC). Using a novel assay method for measuring DOPAL, DOPAC, and dopamine simultaneously, we found that in the putamen of patients with end-stage PD the estimated amount of DOPAL per dopamine terminal was about 10 times control, and ALDH activity, measured by the DOPAC:DOPAL ratio, was about 25% of control. These striking findings are consistent with DOPAL buildup from decreased ALDH activity in the putamen of PD patients. In summary, in PD catecholaminergic denervation in the brain and heart is linked to alpha-synucleinopathy, and post-mortem PD brain features DOPAL buildup and decreased ALDH activity. In the future we hope to develop cellular and animal models to test experimentally whether PD results from pathologic interactions between catecholaldehydes and alpha-synuclein.
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