Top

Published in:

01-06-2018 | Original Paper

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

Authors: Ivan Martinez-Valbuena, Irene Amat-Villegas, Rafael Valenti-Azcarate, Maria del Mar Carmona-Abellan, Irene Marcilla, Maria-Teresa Tuñon, Maria-Rosario Luquin

Published in: Acta Neuropathologica | Issue 6/2018

Abstract

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.

Available only for authorised users

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRef

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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. https://doi.org/10.1111/j.1365-2990.2006.00727.x CrossRefPubMed

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. https://doi.org/10.1016/j.jns.2011.12.008 CrossRefPubMed

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. https://doi.org/10.1016/S0197-4580(02)00065-9 CrossRefPubMed

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. https://doi.org/10.1021/ar200189b CrossRefPubMed

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. https://doi.org/10.1212/WNL.0b013e3182553cc9 CrossRefPubMed

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. https://doi.org/10.1016/S1353-8020(09)70769-2 CrossRefPubMed

16.

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 CrossRefPubMed

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. https://doi.org/10.1038/ncb748 CrossRefPubMed

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. https://doi.org/10.1002/mds.25776 CrossRefPubMed

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. https://doi.org/10.1152/ajpendo.00262.2010 CrossRefPubMed

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. https://doi.org/10.1093/brain/awu369 CrossRefPubMed

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. https://doi.org/10.1073/pnas.1610371113 CrossRefPubMedPubMedCentral

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. https://doi.org/10.1073/pnas.1703420114 PubMedPubMedCentralCrossRef

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. https://doi.org/10.1002/ana.23956 CrossRefPubMed

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. https://doi.org/10.1002/ana.23746 CrossRefPubMed

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. https://doi.org/10.1093/jnen/nlw103 PubMedCrossRef

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. https://doi.org/10.3233/JAD-170192 CrossRef

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. https://doi.org/10.1371/journal.pone.0085781 CrossRefPubMedPubMedCentral

28.

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 CrossRefPubMed

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. https://doi.org/10.1212/01.wnl.0000187889.17253.b1 CrossRefPubMed

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. https://doi.org/10.1038/mp.2016.230 CrossRefPubMedPubMedCentral

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. https://doi.org/10.1084/jem.20161134 PubMedPubMedCentralCrossRef

32.

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 PubMedCrossRefPubMedCentral

33.

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 CrossRefPubMed

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. https://doi.org/10.1093/brain/awv040 CrossRefPubMedPubMedCentral

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. https://doi.org/10.1002/nbm.3066.Non-invasive CrossRef

36.

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 CrossRefPubMed

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. https://doi.org/10.1111/ene.12753 CrossRefPubMed

38.

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 CrossRefPubMedPubMedCentral

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. https://doi.org/10.1016/j.ymeth.2008.06.014 CrossRefPubMed

40.

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 CrossRefPubMed

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. https://doi.org/10.2337/db12-1045 CrossRefPubMedPubMedCentral

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. https://doi.org/10.3233/JAD-160047 CrossRef

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. https://doi.org/10.1016/S1474-4422(16)00080-6 PubMedCrossRef

Title: Interaction of amyloidogenic proteins in pancreatic β cells from subjects with synucleinopathies
Authors: Ivan Martinez-Valbuena
Irene Amat-Villegas
Rafael Valenti-Azcarate
Maria del Mar Carmona-Abellan
Irene Marcilla
Maria-Teresa Tuñon
Maria-Rosario Luquin
Publication date: 01-06-2018
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 6/2018
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-018-1832-0

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

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

Abstract

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 6/2018

Differential α-synuclein expression contributes to selective vulnerability of hippocampal neuron subpopulations to fibril-induced toxicity

The natural HLA ligandome of glioblastoma stem-like cells: antigen discovery for T cell-based immunotherapy

Evidence for altered dendritic spine compartmentalization in Alzheimer’s disease and functional effects in a mouse model

Loss of histone H3K27me3 identifies a subset of meningiomas with increased risk of recurrence

Mutations in LRRK2 amplify cell-to-cell protein aggregate propagation: a hypothesis

Infectious prions do not induce Aβ deposition in an in vivo seeding model