Parkinson’s disease patients experience a wide range of non-motor symptoms that may be provoked by deposits of phosphorylated α-synuclein in the peripheral nervous system. Pre-existing diabetes mellitus might be a risk factor for developing Parkinson’s disease, and indeed, nearly 60% of Parkinson’s disease patients are insulin resistant. Thus, we have investigated whether phosphorylated α-synuclein is deposited in pancreatic tissue of subjects with synucleinopathies. We studied pancreatic tissue from 39 subjects diagnosed with Parkinson’s disease, Lewy body Dementia or incidental Lewy bodies disease, as well as that from 34 subjects with diabetes mellitus and a normal neuropathological examination, and 52 subjects with a normal neuropathological examination. We examined the pancreatic accumulation of phosphorylated α-synuclein and of the islet amyloid polypeptide precursor (IAPP), an amyloidogenic protein that plays an unknown role in diabetes mellitus, but that can promote α-synuclein amyloid deposition in vitro. Moreover, we performed proximity ligation assays to assess whether these two proteins interact in the pancreas of these subjects. Cytoplasmic phosphorylated α-synuclein deposits were found in the pancreatic β cells of 14 subjects with Parkinson’s disease (93%), in 11 subjects with Lewy body Dementia (85%) and in 8 subjects with incidental Lewy body disease (73%). Furthermore, we found similar phosphorylated α-synuclein inclusions in 23 subjects with a normal neuropathological examination but with diabetes mellitus (68%) and in 9 control subjects (17%). In addition, IAPP/α-synuclein interactions appear to occur in patients with pancreatic inclusions of phosphorylated α-synuclein. The presence of phosphorylated α-synuclein inclusions in pancreatic β cells provides a new evidence of a mechanism that is potentially common to the pathogenesis of diabetes mellitus, PD and DLB. Moreover, the interaction of IAPP and α-synuclein in the pancreatic β cells of patients may represent a novel target for the development of strategies to treat these diseases.

帕金森氏病患者会经历多种非运动性症状，这可能是由于周围神经系统中磷酸化的α-突触核蛋白的沉积引起的。先前存在的糖尿病可能是发展帕金森氏病的危险因素，实际上，将近60％的帕金森氏病患者具有胰岛素抵抗性。因此，我们研究了磷酸化的α-突触核蛋白是否沉积在患有突触核蛋白病的受试者的胰腺组织中。我们研究了39名被诊断患有帕金森氏病，路易体性痴呆或偶发性路易体病的受试者的胰腺组织，以及34位糖尿病和神经病理学检查正常的受试者以及52位神经病理学检查正常的受试者的胰腺组织。我们检查了磷酸化α-突触核蛋白和胰岛淀粉样多肽前体（IAPP）的胰腺蓄积，胰岛淀粉样多肽前体（IAPP）是一种淀粉样蛋白，在糖尿病中起未知作用，但可以促进体外α-突触核蛋白的淀粉样沉积。此外，我们进行了邻近结扎分析以评估这两种蛋白质在这些受试者的胰腺中是否相互作用。在14例帕金森氏病患者（93％），11例路易体痴呆患者（85％）和8例路易体偶发疾病（73％）的胰腺β细胞中发现了细胞质磷酸化的α-突触核蛋白沉积物。此外，我们在23名神经病理学检查正常但糖尿病的受试者（68％）和9名对照受试者（17％）中发现了类似的磷酸化α-突触核蛋白包涵体。此外，IAPP /α-突触核蛋白相互作用似乎发生在具有磷酸化α-突触核蛋白的胰腺包涵体的患者中。胰腺β细胞中磷酸化的α-突触核蛋白内含物的存在为糖尿病，PD和DLB的发病机理潜在的共同机制提供了新证据。此外，患者胰岛β细胞中IAPP和α-突触核蛋白的相互作用可能代表了开发治疗这些疾病的策略的新目标。