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.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Adler CH, Beach TG (2016) Neuropathological basis of nonmotor manifestations of Parkinson’s disease. Mov Disord 31:1114–1119. https://doi.org/10.1002/mds.26605
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. https://doi.org/10.1007/s00401-009-0523-2
Athauda D, Foltynie T (2016) Insulin resistance and Parkinson’s disease: a new target for disease modification? Prog Neurobiol 145–146:98–120. https://doi.org/10.1016/j.pneurobio.2016.10.001
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. https://doi.org/10.1016/S0140-6736(17)31585-4
Banks WA, Kastin AJ, Maness LM, Huang W, Jaspan JB (1995) Permeability of the blood-brain barrier to amylin. Life Sci 57:1993–2001. https://doi.org/10.1016/0024-3205(95)02197-Q
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. https://doi.org/10.1159/000112832
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. https://doi.org/10.1186/s40478-016-0408-2
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. https://doi.org/10.1016/j.pneurobio.2014.02.005
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. https://doi.org/10.1007/s00401-010-0664-3
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. https://doi.org/10.1111/j.1365-2990.2006.00727.x
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. https://doi.org/10.1016/j.jns.2011.12.008
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. https://doi.org/10.1016/S0197-4580(02)00065-9
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. https://doi.org/10.1021/ar200189b
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. https://doi.org/10.1212/WNL.0b013e3182553cc9
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. https://doi.org/10.1016/S1353-8020(09)70769-2
Engelender S, Isacson O (2017) the threshold theory for Parkinson’s disease. Trends Neurosci 40:4–14. https://doi.org/10.1016/j.tins.2016.10.008
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. https://doi.org/10.1038/ncb748
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. https://doi.org/10.1002/mds.25776
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. https://doi.org/10.1152/ajpendo.00262.2010
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. https://doi.org/10.1093/brain/awu369
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. https://doi.org/10.1073/pnas.1610371113
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. https://doi.org/10.1073/pnas.1703420114
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. https://doi.org/10.1002/ana.23956
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. https://doi.org/10.1002/ana.23746
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. https://doi.org/10.1093/jnen/nlw103
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. https://doi.org/10.3233/JAD-170192
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. https://doi.org/10.1371/journal.pone.0085781
Lutz TA (2012) Control of energy homeostasis by amylin. Cell Mol Life Sci 69:1947–1965. https://doi.org/10.1007/s00018-011-0905-1
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. https://doi.org/10.1212/01.wnl.0000187889.17253.b1
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. https://doi.org/10.1038/mp.2016.230
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. https://doi.org/10.1084/jem.20161134
Mukherjee A, Soto C (2017) Prion-like protein aggregates and type 2 diabetes. Cold Spring Harb Perspect Med. https://doi.org/10.1101/cshperspect.a024315
Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J et al (2017) Parkinson disease. Nat Rev Dis Prim 3:17013. https://doi.org/10.1038/nrdp.2017.13
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. https://doi.org/10.1093/brain/awv040
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. https://doi.org/10.1002/nbm.3066.Non-invasive
Santiago JA, Potashkin JA (2013) Shared dysregulated pathways lead to Parkinson’s disease and diabetes. Trends Mol Med 19:176–186. https://doi.org/10.1016/j.molmed.2013.01.002
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. https://doi.org/10.1111/ene.12753
Singleton A, Hardy J (2016) The evolution of genetics: alzheimer’s and Parkinson’s diseases. Neuron 90:1154–1163. https://doi.org/10.1016/j.neuron.2016.05.040
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. https://doi.org/10.1016/j.ymeth.2008.06.014
Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840. https://doi.org/10.1038/42166
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. https://doi.org/10.2337/db12-1045
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. https://doi.org/10.3233/JAD-160047
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. https://doi.org/10.1016/S1474-4422(16)00080-6
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.
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.
Electronic supplementary material
Below is the link to the electronic supplementary material.
About this article
Cite this article
Martinez-Valbuena, I., Amat-Villegas, I., Valenti-Azcarate, R. et al. Interaction of amyloidogenic proteins in pancreatic β cells from subjects with synucleinopathies. Acta Neuropathol 135, 877–886 (2018). https://doi.org/10.1007/s00401-018-1832-0
- Parkinson’s disease
- Dementia with Lewy bodies
- Diabetes mellitus