Peripheral synucleinopathy in Parkinson disease with LRRK2 G2385R variants

Abstract

Objective Recent studies demonstrated cutaneous phosphorylated α synuclein (p‐syn) deposition in idiopathic and some monogenetic Parkinson disease (PD) patients, suggesting synucleinopathy identical to that in the brain. Although the LRRK2 Gly2385Arg (G2385R) variant is a common PD risk factor in the Chinese population, the pathogenesis of PD with G2385R variant has not been reported. We investigated whether synucleinopathy and small fiber neuropathy (SFN) are associated with the G2385R variant. Methods We performed genotyping in 59 PD patients and 30 healthy controls from the skin biopsy database. The scale of SFN was assessed, as well as bright‐field immunohistochemistry against antiprotein gene product 9.5 (PGP9.5) and double‐labeling immunofluorescence with anti‐PGP9.5 and anti‐p‐syn. Results (1) p‐syn deposited in the skin nerve fibers of G2385R carrier PD patients, which was a different pattern from noncarriers, without no difference observed between proximal and distal regions; (2) decreased distal intraepidermal nerve fiber density was found in both the G2385R carrier and the noncarrier PD group, and was negatively correlated with composite autonomic symptom score‐31 item (COMPASS‐31) scores; (3) PD patients with the G2385R variant showed a more peculiar clinical profile than noncarriers with a higher nonmotor symptoms scale, COMPASS‐31 score, and levodopa equivalent dose, in addition to an increased prevalence of certain autonomic symptoms or rapid eye movement sleep behavior disorders. Interpretation Synucleinopathy is related to the LRRK2 G2385R genotype and implies a different pathogenesis in G2385R variant carriers and noncarriers. This study also extended the clinical profiles of PD patients with the G2385R variant.

α‐Synuclein Deposition in Sympathetic Nerve Fibers in Genetic Forms of Parkinson's Disease

“…Yang et al 23 recently reported that patients carrying the LRRK2 risk variant G2385R have phosphorylated α‐syn deposition in the skin similar to patients without the variant. This variant increases the risk for PD by about twofold and is present in about 2% of the East Asian population, according to the Genome Aggregation Database (gnomAD) v.2.1.1 24‐26 .…”

Skin alpha-synuclein deposit patterns: A predictor of Parkinson's disease subtypes

“…In the Chinese population it may increase PD risk by nearly two-fold. 38 Both cellular and animal model studies have found that LRRK2 plays a role in kinase activity and may cause α-syn to be phosphorylated. 39 Kinase activity is elevated in individuals with Gly2019Ser or Ile2020Thr mutations, which cause PD via “gain‐of‐function” or hyperactivity of LRRK2 .…”

“… 40 Compared with idiopathic PD (iPD) patients, patients with the LRRK2 G2385R variant require a larger levodopa equivalent dose and manifest a specific clinical profile including gait dysfunction and postural instability, motor fluctuations, fatigue, and rapid eye movement sleep behavior disorders. 38 …”

“…Notably, the nonmotor symptoms scale (NMSS) score, percentage of patients with rapid eye movement sleep behavior disorders (RBD), and levodopa equivalent dose (LED) were all higher in the G2385R carrier group than the noncarrier group. 38 However, there are no prior studies about the correlation between p-α-syn deposition and clinical outcomes. These results may suggest that the distribution pattern of skin p-α-syn in PD patients with the LRRK2 G2385R variant is homogeneous, whereas PD patients without this variant show a p-α-syn distribution with a proximal-distal gradient.…”

Pathophysiological evaluation of the LRRK2 G2385R risk variant for Parkinson’s disease

“…Heterogeneous brain pathology is a feature of LRRK2 -linked PD 2 , 26 , 27 ; as such, knowing whether there is a correlation between LRRK2 variants in each domain and specific pathology is an important approach that will contribute to our understanding of the pathogenesis of LRRK2 -linked PD. Although a skin biopsy study reports that synucleinopathy is associated with LRRK2 G2385R 28 , no brain autopsy of PD with LRRK2 G2385R has been reported. Here, we report a PD case with LRRK2 G2385R wherein a typical diffuse Lewy body disease pathology with mild gliosis, possibly caused by increased LRRK2 kinase activity in the brain was observed.…”