Autonomic Medicine Section, Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Inherited Disorders Unit, Neurogenetics Branch, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Mov Disord. 2021 Oct;36(10):2346-2357. doi: 10.1002/mds.28667. Epub 2021 Jun 2.
Cytoplasmic inclusions of α-synuclein (α-syn) in brainstem neurons are characteristic of idiopathic Parkinson's disease (PD). PD also entails α-syn buildup in sympathetic nerves. Among genetic forms of PD, the relative extents of sympathetic intraneuronal accumulation of α-syn have not been reported.
This cross-sectional observational study compared magnitudes of intraneuronal deposition of α-syn in common and rare genetic forms of PD.
α-Syn deposition was quantified by the α-syn-tyrosine hydroxylase colocalization index in C2 cervical skin biopsies from 65 subjects. These included 30 subjects with pathogenic mutations in SNCA (n = 3), PRKN [biallelic (n = 7) and monoallelic (n = 3)], LRRK2 (n = 7), GBA (n = 7), or PARK7/DJ1 [biallelic (n = 1) and monoallelic (n = 2)]. Twenty-five of the mutation carriers had PD and five did not. Data were also analyzed from 19 patients with idiopathic PD and 16 control participants.
α-Syn deposition varied as a function of genotype (F = 16.7, P < 0.0001). It was above the control range in 100% of subjects with SNCA mutations, 100% with LRRK2 mutations, 95% with idiopathic PD, 83% with GBA mutations, and 0% with biallelic PRKN mutations. α-Syn deposition in the biallelic PRKN group was significantly higher than in the control group. In addition, patients with biallelic PRKN mutations had higher α-syn deposition than their unaffected siblings.
Individuals with SNCA, DJ-1, LRRK2, or GBA mutations have substantial intraneuronal α-syn deposition in sympathetic noradrenergic nerves in skin biopsies, whereas those with biallelic PRKN mutations do not. Biallelic PRKN patients may have mildly increased α-syn deposition compared with control subjects. © 2021 International Parkinson and Movement Disorder Society.
α-突触核蛋白（α-syn）在脑干神经元中的细胞质包涵体是特发性帕金森病（PD）的特征。PD 还伴有交感神经中的 α-syn 堆积。在 PD 的遗传形式中，尚未报道交感神经内 α-syn 的累积程度。
本横断面观察性研究比较了常见和罕见遗传形式 PD 中神经元内 α-syn 沉积的程度。
通过 C2 颈椎皮肤活检中 α-syn-酪氨酸羟化酶共定位指数对 65 名受试者进行 α-syn 沉积定量。其中包括 30 名 SNCA 致病性突变受试者（n=3）、PRKN [双等位基因（n=7）和单等位基因（n=3）]、LRRK2（n=7）、GBA（n=7）或 PARK7/DJ1 [双等位基因（n=1）和单等位基因（n=2）]。25 名突变携带者患有 PD，5 名没有。还分析了 19 名特发性 PD 患者和 16 名对照参与者的数据。
α-syn 沉积随基因型而变化（F=16.7，P<0.0001）。SNCA 突变者、LRRK2 突变者、特发性 PD 患者、GBA 突变者和 PRKN 双等位基因突变者 100%的受试者α-syn 沉积均高于对照范围。PRKN 双等位基因组的 α-syn 沉积显著高于对照组。此外，PRKN 双等位基因突变的患者比未受影响的兄弟姐妹有更高的 α-syn 沉积。
SNCA、DJ-1、LRRK2 或 GBA 突变的个体在皮肤活检的交感去甲肾上腺素神经中具有大量的神经元内 α-syn 沉积，而 PRKN 双等位基因突变的个体则没有。与对照组相比，PRKN 双等位基因患者的 α-syn 沉积可能略有增加。
