To assess the extent of peripheral synucleinopathy in genetic Parkinson’s disease (PD).

Deposits of α-synuclein (α-syn) in the brainstem characterize idiopathic PD (iPD) and are also found in autonomic nerve fibers in the skin. The extent of intra-neuronal synucleinopathy in genetic forms of PD has been less clear. Here we describe the first series to directly compare peripheral synucleinopathy in the most common genetic PD subtypes, LRRK2, GBA, Parkin, SNCA, and DJ1.

α-Syn deposition in sympathetic noradrenergic neurons was quantified by the α-syn-tyrosine hydroxylase (TH) colocalization index in C2 cervical skin biopsies from 65 subjects. These included 30 subjects with pathogenic mutations in SNCA (N=3), Parkin (biallelic [N=7] or monoallelic [N=3]), LRRK2 (N=7), GBA (N=7), or DJ1 (N=3); 19 iPD patients; 12 patients with unrelated diseases (UD); and 4 healthy volunteers (HV).

Values for α-syn-TH colocalization indices varied according to genotype. Intraneuronal α-syn deposition greater than the control (CTRL=HV+UD) range was observed for all SNCA and LRRK2 participants and the majority of GBA (83%) and iPD (95%) participants. In contrast, no biallelic Parkin participants had high α-syn-TH colocalization indices. Increased α-syn deposition was observed in an asymptomatic SNCA duplication carrier but not a homozygous GBA participant without PD, suggesting that prodromal peripheral synucleinopathy may be present in some but not all genetic forms of PD. Colocalization indices in patients with biallelic LRRK2 mutations or digenic for LRRK2 and GBA mutations were similar to those with a single LRRK2 or GBA mutation.

Individuals with SNCA, DJ-1, LRRK2, or GBA genotypic abnormalities have increased α-syn deposition in sympathetic noradrenergic nerves, whereas those with Parkin abnormalities do not. Surprisingly, presence or absence of peripheral synucleinopathy was consistent among patients with LRRK2 or Parkin mutations, in contrast to the variable brainstem synucleinopathy reported for such patients in autopsy series.