Acta Neuropathologica

, Volume 135, Issue 6, pp 877–886 | Cite as

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

  • Ivan Martinez-Valbuena
  • Irene Amat-Villegas
  • Rafael Valenti-Azcarate
  • Maria del Mar Carmona-Abellan
  • Irene Marcilla
  • Maria-Teresa Tuñon
  • Maria-Rosario LuquinEmail author
Original Paper


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.


Alpha-synuclein Parkinson’s disease Dementia with Lewy bodies Diabetes mellitus IAPP Cross-seeding 



This study was funded in part by the Instituto de Salud Carlos III (PI15/01816 to MRL), and to the generous contribution of A. Arroqui and J.L. Arroqui to MRL research. IMV was supported by the “Asociación de Amigos de la Universidad de Navarra” and “la Caixa” Bank Foundation. We particularly wish to acknowledge the invaluable technical support of Laura Alonso-Herrero, Dr. Maria Hernandez-Sanchez, and Dr. Iria Gonzalez-Dopeso.

Compliance with ethical standards

Conflict of interest

IAV received remuneration from Merck Sharp & Dohme (MDS) for activities unrelated to the work submitted. MRL received remuneration from TEVA, Zambon, AbbVie, and Bial for activities unrelated to the work submitted. The other authors have no conflicts of interests to declare.

Supplementary material

401_2018_1832_MOESM1_ESM.docx (44.3 mb)
Supplementary material 1 (DOCX 45403 kb)


  1. 1.
    Adler CH, Beach TG (2016) Neuropathological basis of nonmotor manifestations of Parkinson’s disease. Mov Disord 31:1114–1119. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Alafuzoff I, Ince PG, Arzberger T, Al-Sarraj S, Bell J, Bodi I et al (2009) Staging/typing of Lewy body related α-synuclein pathology: a study of the BrainNet Europe Consortium. Acta Neuropathol 117:635–652. CrossRefPubMedGoogle Scholar
  3. 3.
    Athauda D, Foltynie T (2016) Insulin resistance and Parkinson’s disease: a new target for disease modification? Prog Neurobiol 145–146:98–120. CrossRefPubMedGoogle Scholar
  4. 4.
    Athauda D, Maclagan K, Skene SS, Bajwa-Joseph M, Letchford D, Chowdhury K et al (2017) Exenatide once weekly versus placebo in Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet 6736:1–12. CrossRefGoogle Scholar
  5. 5.
    Banks WA, Kastin AJ, Maness LM, Huang W, Jaspan JB (1995) Permeability of the blood-brain barrier to amylin. Life Sci 57:1993–2001. CrossRefPubMedGoogle Scholar
  6. 6.
    Barbour R, Kling K, Anderson JP, Banducci K, Cole T, Diep L et al (2008) Red blood cells are the major source of alpha-synuclein in blood. Neurodegener Dis 5:55–59. CrossRefPubMedGoogle Scholar
  7. 7.
    Barrenschee M, Zorenkov D, Böttner M, Lange C, Cossais F, Scharf AB et al (2017) Distinct pattern of enteric phospho-alpha-synuclein aggregates and gene expression profiles in patients with Parkinson’s disease. Acta Neuropathol Commun 5:1. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Bassil F, Fernagut PO, Bezard E, Meissner WG (2014) Insulin, IGF-1 and GLP-1 signaling in neurodegenerative disorders: targets for disease modification? Prog Neurobiol 118:1–18. CrossRefPubMedGoogle Scholar
  9. 9.
    Beach TG, Adler CH, Sue LI, Vedders L, Lue LF, White CL et al (2010) Multi-organ distribution of phosphorylated α-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol 119:689–702. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Bloch A, Probst A, Bissig H, Adams H, Tolnay M (2006) α-Synuclein pathology of the spinal and peripheral autonomic nervous system in neurologically unimpaired elderly subjects. Neuropathol Appl Neurobiol 32:284–295. CrossRefPubMedGoogle Scholar
  11. 11.
    Bosco D, Plastino M, Cristiano D, Colica C, Ermio C, De Bartolo M et al (2012) Dementia is associated with insulin resistance in patients with Parkinson’s disease. J Neurol Sci 315:39–43. CrossRefPubMedGoogle Scholar
  12. 12.
    Braak H, Del Tredici K, Rüb U, De Vos RAI, Jansen Steur ENH, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211. CrossRefPubMedGoogle Scholar
  13. 13.
    Brender JR, Salamekh S, Ramamoorthy A (2012) Membrane disruption and early events in the aggregation of the diabetes related peptide IAPP from a molecular perspective. Acc Chem Res 45:454–462. CrossRefPubMedGoogle Scholar
  14. 14.
    Cereda E, Barichella M, Cassani E, Caccialanza R, Pezzoli G (2012) Clinical features of Parkinson disease when onset of diabetes came first: a case-control study. Neurology 78:1507–1511. CrossRefPubMedGoogle Scholar
  15. 15.
    Dickson DW, Fujishiro H, Orr C, DelleDonne A, Josephs K, Frigerio R et al (2009) Neuropathology of non-motor features of Parkinson disease. Parkinsonism Relat Disord 15(Suppl 3):S1–S5. CrossRefPubMedGoogle Scholar
  16. 16.
    Engelender S, Isacson O (2017) the threshold theory for Parkinson’s disease. Trends Neurosci 40:4–14. CrossRefPubMedGoogle Scholar
  17. 17.
    Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg MS et al (2002) α-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 4:160–164. CrossRefPubMedGoogle Scholar
  18. 18.
    Gelpi E, Navarro-Otano J, Tolosa E, Gaig C, Compta Y, Rey MJ et al (2014) Multiple organ involvement by alpha-synuclein pathology in Lewy body disorders. Mov Disord 29:1010–1018. CrossRefPubMedGoogle Scholar
  19. 19.
    Geng X, Lou H, Wang J, Li L, Swanson AL, Sun M et al (2011) α-Synuclein binds the K(ATP) channel at insulin-secretory granules and inhibits insulin secretion. Am J Physiol Endocrinol Metab 300:E276–E286. CrossRefPubMedGoogle Scholar
  20. 20.
    Gjerløff T, Fedorova T, Knudsen K, Munk OL, Nahimi A, Jacobsen S et al (2015) Imaging acetylcholinesterase density in peripheral organs in Parkinson’s disease with 11 C-donepezil PET. Brain 138:653–663. CrossRefPubMedGoogle Scholar
  21. 21.
    Horvath I, Wittung-Stafshede P (2016) Cross-talk between amyloidogenic proteins in type-2 diabetes and Parkinson’s disease. Proc Natl Acad Sci USA 113:12473–12477. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Íñigo-Marco I, Valencia M, Larrea L, Bugallo R, Martínez-Goikoetxea M, Zuriguel I et al (2017) E46K α-synuclein pathological mutation causes cell-autonomous toxicity without altering protein turnover or aggregation. Proc Natl Acad Sci. PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Jackson K, Barisone GA, Diaz E, Jin LW, DeCarli C, Despa F (2013) Amylin deposition in the brain: a second amyloid in Alzheimer disease? Ann Neurol 74:517–526. CrossRefPubMedGoogle Scholar
  24. 24.
    Kalia LV, Kalia SK, McLean PJ, Lozano AM, Lang AE (2013) α-Synuclein oligomers and clinical implications for parkinson disease. Ann Neurol 73:155–169. CrossRefPubMedGoogle Scholar
  25. 25.
    Lee JM, Derkinderen P, Kordower JH, Freeman R, Munoz DG, Kremer T et al (2017) The search for a peripheral biopsy indicator of α-synuclein pathology for Parkinson disease. J Neuropathol Exp Neurol 76:2–15. PubMedCrossRefGoogle Scholar
  26. 26.
    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. CrossRefGoogle Scholar
  27. 27.
    Lu L, Fu D-L, Li H-Q, Liu A-J, Li J-H, Zheng G-Q (2014) Diabetes and risk of Parkinson’s disease: an updated meta-analysis of case-control studies. PLoS ONE 9:e85781. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Lutz TA (2012) Control of energy homeostasis by amylin. Cell Mol Life Sci 69:1947–1965. CrossRefPubMedGoogle Scholar
  29. 29.
    McKeith IG, Dickson DW, Lowe J, Emre M, O’Brien JT, Feldman H et al (2005) Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65:1863–1872. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Moreno-Gonzalez I, Edwards G III, Salvadores N, Shahnawaz M, Diaz-Espinoza R, Soto C (2017) Molecular interaction between type 2 diabetes and Alzheimer’s disease through cross-seeding of protein misfolding. Mol Psychiatry 22:1327–1334. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Mukherjee A, Morales-Scheihing D, Salvadores N, Moreno-Gonzalez I, Gonzalez C, Taylor-Presse K et al (2017) Induction of IAPP amyloid deposition and associated diabetic abnormalities by a prion-like mechanism. J Exp Med. PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Mukherjee A, Soto C (2017) Prion-like protein aggregates and type 2 diabetes. Cold Spring Harb Perspect Med. PubMedCrossRefGoogle Scholar
  33. 33.
    Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J et al (2017) Parkinson disease. Nat Rev Dis Prim 3:17013. CrossRefPubMedGoogle Scholar
  34. 34.
    Roberts RF, Wade-Martins R, Alegre-Abarrategui J (2015) Direct visualization of alpha-synuclein oligomers reveals previously undetected pathology in Parkinson’s disease brain. Brain 138:1642–1657. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Sang Ryong K, Vicent R, Hsiao-Chun C, Tatyana K, Tinmarla F, Karen D et al (2011) Age and alpha-synuclein expression interact to reveal a dependence of dopaminergic axons on edogenous Akt/PKB signaling. Neurobiol Dis 44:215–222. CrossRefGoogle Scholar
  36. 36.
    Santiago JA, Potashkin JA (2013) Shared dysregulated pathways lead to Parkinson’s disease and diabetes. Trends Mol Med 19:176–186. CrossRefPubMedGoogle Scholar
  37. 37.
    Schneider SA, Boettner M, Alexoudi A, Zorenkov D, Deuschl G, Wedel T (2016) Can we use peripheral tissue biopsies to diagnose Parkinson’s disease? A review of the literature. Eur J Neurol 23:247–261. CrossRefPubMedGoogle Scholar
  38. 38.
    Singleton A, Hardy J (2016) The evolution of genetics: alzheimer’s and Parkinson’s diseases. Neuron 90:1154–1163. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Söderberg O, Leuchowius K-J, Gullberg M, Jarvius M, Weibrecht I, Larsson L-G et al (2008) Characterizing proteins and their interactions in cells and tissues using the in situ proximity ligation assay. Methods 45:227–232. CrossRefPubMedGoogle Scholar
  40. 40.
    Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840. CrossRefPubMedGoogle Scholar
  41. 41.
    Steneberg P, Bernardo L, Edfalk S, Lundberg L, Backlund F, Östenson CG et al (2013) The type 2 diabetes-associated gene Ide is required for insulin secretion and suppression of α-synuclein levels in β-cells. Diabetes 62:2004–2014. CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Verma N, Ly H, Liu M, Chen J, Zhu H, Chow M et al (2016) Intraneuronal amylin deposition, peroxidative membrane injury and increased IL-1β synthesis in brains of Alzheimer’s disease patients with type-2 diabetes and in diabetic HIP rats. J Alzheimer’s Dis 53:259–272. CrossRefGoogle Scholar
  43. 43.
    Vilas D, Iranzo A, Tolosa E, Aldecoa I, Berenguer J, Vilaseca I et al (2016) Assessment of α-synuclein in submandibular glands of patients with idiopathic rapid-eye-movement sleep behaviour disorder: a case-control study. Lancet Neurol. PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Ivan Martinez-Valbuena
    • 1
    • 2
    • 3
  • Irene Amat-Villegas
    • 3
    • 4
  • Rafael Valenti-Azcarate
    • 1
    • 2
    • 3
  • Maria del Mar Carmona-Abellan
    • 1
    • 2
    • 3
  • Irene Marcilla
    • 2
    • 3
  • Maria-Teresa Tuñon
    • 3
    • 4
  • Maria-Rosario Luquin
    • 1
    • 2
    • 3
    Email author
  1. 1.Neurology DepartmentClinica Universidad de NavarraPamplonaSpain
  2. 2.Regenerative Therapy Laboratory, Neurosciences Division, Center for Applied Medical Research (CIMA)University of NavarraPamplonaSpain
  3. 3.Navarra’s Health Research Institute (IDISNA)PamplonaSpain
  4. 4.Pathology DepartmentComplejo Hospitalario de NavarraPamplonaSpain

Personalised recommendations