Small fiber neuropathy and phosphorylated alpha-synuclein in the skin of E46K-SNCA mutation carriers
Small fiber neuropathy and phosphorylated alpha-synuclein in the skin of E46K-SNCA mutation carriers
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DOI：
10.1016/j.parkreldis.2019.05.038
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发表时间：
2019-08-01
影响因子：
4.1
通讯作者：
Carlos Gomez-Esteban, Juan
中科院分区：
文献类型：
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作者：
Carmona-Abellan, Mar;Gabilondo, Inigo;Carlos Gomez-Esteban, Juan
背景和目的：在2004年，我们描述了α-突触核蛋白基因中的E46K突变（E46K-SNCA），这是一种罕见的点突变，可导致具有早期突出的非运动特征和心肌小纤维去神经支配的侵袭性路易体病。考虑到皮肤作为开发帕金森病（PD）生物标志物的靶点的潜在利益，在这项工作中，我们旨在评估小自主神经纤维和磷酸化α-突触核蛋白的结构和功能完整性与在帕金基因突变（PARK2）携带者和健康对照中观察到的那些相比，E46K-SNCA携带者的皮肤中的β-突触核蛋白（β-synuclein）沉积。我们研究了7个E46K-SNCA载体，（3例路易体痴呆，2例单纯自主神经功能衰竭，1例PD和1例无症状），2例PARK 2携带者和2例健康对照，用颈部皮肤穿刺活检定量表皮内神经纤维密度和p-突触核蛋白沉积（抗PGP9.5/UCHL-1、TH和p-突触核蛋白的免疫组织化学）和具有电化学皮肤电导（ESC）的催汗功能结果：所有E46 K-SNCA携带者在不同的表皮和真皮结构（包括神经束和腺体）中具有中度至重度的p-突触核蛋白沉积和小纤维神经变性，尤其是在具有纯自主神经功能衰竭的携带者中，而在健康对照和两个PARK2携带者中的一个中不存在p-突触核蛋白聚集体。E46K-SNCA中的后者皮肤异常的严重程度与手中的泌汗功能障碍（下ESC）相关（p = 0.035）。解释：这些结果与我们先前的发现一起支持E46K-SNCA突变作为研究路易体疾病中的小纤维神经病的合适模型的相关性。
Background and objective: In 2004 we described the E46K mutation in alpha-synuclein gene (E46K-SNCA), a rare point mutation causing an aggressive Lewy body disease with early prominent non-motor features and small fiber denervation of myocardium. Considering the potential interest of the skin as a target for the development of biomarkers in Parkinson's Disease (PD), in this work we aimed to evaluate structural and functional integrity of small autonomic nerve fibers and phosphorylated alpha-synuclein (p-synuclein) deposition in the skin of E46K-SNCA carriers as compared to those observed in parkin gene mutation (PARK2) carriers and healthy controls.Patients and methods: We studied 7 E46K-SNCA carriers (3 dementia with Lewy bodies, 2 pure autonomic failure, 1 PD and 1 asymptomatic), 2 PARK2 carriers and 2 healthy controls to quantify intraepidermal nerve fiber density and p-synuclein deposition with cervical skin punch biopsies (immunohistochemistry against anti PGP9.5/UCHL-1, TH and p-synuclein) and sudomotor function with electrochemical skin conductance (ESC) (SudoScan).Results: All E46K-SNCA carriers had moderate to severe p-synuclein deposits and small fiber neurodegeneration in different epidermal and dermal structures including nerve fascicles and glands, especially in carriers with Pure Autonomic Failure, while p-synuclein aggregates where absent in healthy controls and in one of two PARK2 carriers. The severity of the latter skin abnormalities in E46K-SNCA were correlated with sudomotor dysfunction (lower ESC) in hands (p = 0.035).Interpretation: These results together with our previous findings support the relevance of E46K-SNCA mutation as a suitable model to study small fiber neuropathy in Lewy body diseases.