Is Ross Syndrome a New Type of Synucleinopathy? A Brief Research Report

Abstract

Ross syndrome (RS) is a rare peripheral autonomic system disorder characterized by tonic pupil, hyporeflexia, and segmental anhidrosis. Neuropathological studies show that RS results from the selective cholinergic nerve degeneration. However, the cause and underlying mechanisms are largely unknown. Here, we show α-synuclein accumulation in the autonomic nerve terminals in the lesser curvature of stomach of patients with RS. In addition, immunohistochemical findings demonstrate that a dominant degeneration of cholinergic fibers is exhibited in patients with RS, while main degeneration of adrenergic fibers is demonstrated in patients with pure autonomic failure in their gastrointestinal and urinary system. Our study suggests that RS belongs to α-synucleinopathies. Moreover, our findings indicate that adrenergic nerves and cholinergic nerves are not equally damaged in different types of pure autonomic dysfunctions.

Keywords: autonomic dysfunction; neuropathology; peripheral autonomic system disorder; pure autonomic failure; α-synucleinopathy.

FIGURE 1

Morphologic and functional features of patients and normal controls. (A) Thermoregulatory sweat test (iodine-starch method). Hypohidrosis is seen mainly on the right side of the face. (B) Digital infrared thermal imaging shows a lower temperature in the left side of the face than the right. (C) Pupillary light reflex appears sluggish in the right eye, but normal in the left eye. (D–G) VIP immunoreactive fibers appeared more frequently in the skin of normal controls (D,E) than in Ross patients (F,G). In Ross patients, rare VIP immunoreactive fibers were found around sweat glands in anhidrotic skin (F), while VIP-ir fibers appeared more frequently in hyperhidrotic skin (G). (H–K). The PGP 9.5-ir fibers appeared more frequently in the skin of normal controls (H,I) than in Ross patients (J,K). In Ross patients, the PGP 9.5-ir fibers were severely reduced in anhidrotic skin (J) and slightly reduced in hyperhidrotic skin (K).

FIGURE 2

Pathological α-Syn immunoreactivity in patients with Ross syndrome, PAF PD, MSA, and normal controls. (A–D,I–P) Some of fibers were positive for pα-Syn inclusions (A,B,I,J) or α-Syn filament (C,D,K,L) in anhidrotic skin (A–D) and lesser curvature of stomach (I–L). (M–P) α-Syn filament was present in lesser curvature of stomach in PAF (M) and PD (N), but not in MSA (O) and normal controls (P). (E–H,Q–T) Double immunofluorescence analysis showed that pα-Syn colocalized with panaxonal marker PGP 9.5 in the skin (E–H) and lesser curvature of stomach (Q–T) from the patients with RS. Bar = 100 μm.

FIGURE 3

Histopathological features in patients with Ross syndrome, PAF, and normal controls. (A–F) Double immunofluorescence analysis of lesser curvature of stomach: Nerve fibers are marked in green using PGP 9.5; cholinergic fibers and adrenergic fibers are stained in red by anti-VIP and anti-TH antibodies. VIP-ir fibers appear poorly represented in RS (A), while they were evident in PAF (B) and normal controls (C). TH-ir fibers were present in Ross patients (D) and normal controls (F), while they were reduced in PAF (E). (G,H) Double immunofluorescence analysis of lesser curvature of stomach; VIP-ir pα-Syn (G) appeared more frequently than TH-ir pα-Syn (H). (I–N) Double immunofluorescence study of urinary bladder innervation. VIP-ir fibers appear poorly represented in RS (I), while they were evident in PAF (J) and normal controls (K). TH-ir fibers were present in Ross patients (L) and normal controls (N), while they were reduced in PAF (M). (O,P) Quantification of VIP-ir fibers and TH-ir fibers in the lesser curvature of stomach (O) and bladder (P), respectively. Bar = 100 μm. *P < 0.05.