Interaction of amyloidogenic proteins in pancreatic β cells from subjects with synucleinopathies

Parkinson's disease patients experience a wide range of non-motor symptoms that may be provoked by deposits of phosphorylated alpha-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 alpha-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 alpha-synuclein and of the islet amyloid polypeptide precursor (IAPP), an amyloidogenic protein that plays an unknown role in diabetes mellitus, but that can promote alpha-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 alpha-synuclein deposits were found in the pancreatic beta 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 alpha-synuclein inclusions in 23 subjects with a normal neuropathological examination but with diabetes mellitus (68%) and in 9 control subjects (17%). In addition, IAPP/alpha-synuclein interactions appear to occur in patients with pancreatic inclusions of phosphorylated alpha-synuclein. The presence of phosphorylated alpha-synuclein inclusions in pancreatic beta 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 alpha-synuclein in the pancreatic beta cells of patients may represent a novel target for the development of strategies to treat these diseases.