Pathophysiological significance of increased α-synuclein deposition in sympathetic nerves in Parkinson disease: A post-mortem observational study

Background: Parkinson disease (PD) is characterized by intra-neuronal deposition of the protein α-synuclein (α-syn) and by deficiencies of the catecholamines dopamine and norepinephrine (NE) in the brain and heart. Accumulation of α-syn in sympathetic noradrenergic nerves may provide a useful PD biomarker; however, whether α-syn buildup is pathophysiological has been unclear. If it were, one would expect associations of intra-neuronal α-syn deposition with catecholaminergic denervation and with decreased NE contents in the same samples. Methods: We assayed immunoreactive α-syn and tyrosine hydroxylase (TH, a marker of catecholaminergic innervation) concurrently with catecholamines in coded post-mortem scalp skin, submandibular gland (SMG), and apical left ventricular myocardial tissue samples from 14 patients with autopsy-proven PD and 12 age-matched control (CTRL) subjects who did not have a neurodegenerative disease. Results: PD patients had increased α-syn in sympathetic noradrenergically innervated arrector pili muscles (5.7 times CTRL, p<0.0001), SMG (35 times CTRL, p=0.0011), and myocardium (11 times CTRL, p=0.0011). Myocardial TH in the PD group was decreased from CTRL by 65% (p=0.0008), whereas the groups did not differ in TH in either arrector pili muscles or SMG. Similarly, myocardial NE was decreased by 92% in the PD group (p<0.0001), but the groups did not differ in NE in either scalp skin or SMG. Conclusions: PD entails increased α-syn in skin, SMG, and myocardial tissues. In skin and SMG augmented α-syn deposition in sympathetic nerves does not seem to be pathogenic. The pathophysiological significance of intra-neuronal α-syn deposition appears to be organ-selective and prominent in the heart.