Objective: We have investigated whether deposits of phosphorylated TDP-43 might be present in pancreatic tissue of patients with synucleinopathies.

Background: The TAR DNA binding protein of 43 kDa (TDP-43) has been shown to be associated with neurodegenerative diseases, including frontotemporal lobar degeneration and amyotrophic lateral sclerosis and Alzheimer’s disease. A handful of studies have also shown that TDP-43 positive inclusions are also found in some Parkinson’s disease brains. Although little is known about its role in neurodegeneration, recently it has been described an association between pancreatic levels of islet amyloid polypeptide precursor (IAPP) and brain TDP-43 inclusions in subjects with neurodegenerative diseases. To date, the presence of phosphorylated TDP-43 inclusions outside the brain has never been explored.

Methods: We included pancreatic tissue and the amygdala from 39 subjects diagnosed with Parkinson’s disease, Lewy body Dementia or incidental Lewy bodies disease, as well as that from 34 neurologically asymptomatic subjects with diabetes mellitus and 52 control subjects. We assess the accumulation of both TDP-43 and phosphorylated TDP-43 in both tissues. Moreover, we performed proximity ligation assays to assess whether this protein interact in the pancreas of these subjects with the IAPP, an amyloidogenic protein that plays an unknown role in diabetes mellitus pathophysiology but that can cross-seed with other proteins to promote the formation of oligomeric species.

Results: We observed cytoplasmic phosphorylated TDP-43 deposits in pancreatic β cells of 7 subjects with Parkinson’s Disease (47%), in 6 subjects with Lewy Body Dementia (50%) and in 3 subjects with incidental Lewy bodies disease (25%). Furthermore, we found the same phosphorylated TDP-43 inclusions in 14 neurologically asymptomatic subjects with diabetes mellitus (42%) and in 7 control subjects (15%). In addition, we discover an IAPP/TDP-43 interaction in patients with phosphorylated TDP-43 pancreatic inclusions.

Conclusions: Our study shows for the first time that pancreatic beta cells of some patients either with a synucleinopathy or with T2DM antecedent have cytoplasmic phosphorylated TDP-43 inclusions. Its interaction with the IAPP protein, and the role of these phosphorylated TDP-43 inclusions in the physiopathology of PD, DLB and T2DM will be further discussed.

References: 1. Leino M, Popova SN, Alafuzoff I (2017) Transactive DNA Binding Protein 43 Rather Than Other Misfolded Proteins in the Brain is Associated with Islet Amyloid Polypeptide in Pancreas in Aged Subjects with Diabetes Mellitus. J Alzheimer’s Dis xx. doi: 10.3233/JAD-170192.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/interaction-of-tdp-43-with-iapp-in-pancreatic-beta-cells-of-patients-with-sinucleinopathies/