Top

Published in:

01-02-2020 | Disorders of Intellectual Development | Original Paper

Loss of fragile X mental retardation protein precedes Lewy pathology in Parkinson’s disease

Authors: Yi Tan, Carmelo Sgobio, Thomas Arzberger, Felix Machleid, Qilin Tang, Elisabeth Findeis, Jorg Tost, Tasnim Chakroun, Pan Gao, Mathias Höllerhage, Kai Bötzel, Jochen Herms, Günter Höglinger, Thomas Koeglsperger

Published in: Acta Neuropathologica | Issue 2/2020

Abstract

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder and is characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) and the gradual appearance of α-synuclein (α-syn)-containing neuronal protein aggregates. Although the exact mechanism of α-syn-mediated cell death remains elusive, recent research suggests that α-syn-induced alterations in neuronal excitability contribute to cell death in PD. Because the fragile X mental retardation protein (FMRP) controls the expression and function of numerous neuronal genes related to neuronal excitability and synaptic function, we here investigated the role of FMRP in α-syn-associated pathological changes in cell culture and mouse models of PD as well as in post-mortem human brain tissue from PD patients. We found FMRP to be decreased in cultured DA neurons and in the mouse brain in response to α-syn overexpression. FMRP was, furthermore, lost in the SNc of PD patients and in patients with early stages of incidental Lewy body disease (iLBD). Unlike fragile X syndrome (FXS), FMR1 expression in response to α-syn was regulated by a mechanism involving Protein Kinase C (PKC) and cAMP response element-binding protein (CREB). Reminiscent of FXS neurons, α-syn-overexpressing cells exhibited an increase in membrane N-type calcium channels, increased phosphorylation of ERK1/2, eIF4E and S6, increased overall protein synthesis, and increased expression of Matrix Metalloproteinase 9 (MMP9). FMRP affected neuronal function in a PD animal model, because FMRP-KO mice were resistant to the effect of α-syn on striatal dopamine release. In summary, our results thus reveal a new role of FMRP in PD and support the examination of FMRP-regulated genes in PD disease progression.

Available only for authorised users

Alisch RS, Wang T, Chopra P, Visootsak J, Conneely KN, Warren ST (2013) Genome-wide analysis validates aberrant methylation in fragile × syndrome is specific to the FMR1 locus. BMC Med Genet 14:1. https://doi.org/10.1186/1471-2350-14-18 CrossRef

Aryee MJ, Jaffe AE, Corrada-Bravo H, Ladd-Acosta C, Feinberg AP, Hansen KD, Irizarry RA (2014) Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics 30:1363–1369. https://doi.org/10.1093/bioinformatics/btu049 CrossRefPubMedPubMedCentral

Ashley CT, Wilkinson KD, Reines D, Warren ST (1993) FMR1 protein: conserved RNP family domains and selective RNA binding. Science 262:563–566CrossRefPubMed

Berg D, Postuma RB, Bloem B, Chan P, Dubois B, Gasser T, Goetz CG, Halliday GM, Hardy J, Lang AE, Litvan I, Marek K, Obeso J, Oertel W, Olanow CW, Poewe W, Stern M, Deuschl G (2014) Time to redefine PD? Introductory statement of the MDS Task Force on the definition of Parkinson’s disease. Mov Disord 29:454–462. https://doi.org/10.1002/mds.25844 CrossRefPubMedPubMedCentral

Bhakar AL, Dölen G, Bear MF (2012) The Pathophysiology of Fragile × (and what it teaches us about synapses). Annu Rev Neurosci 35:417–443. https://doi.org/10.1146/annurev-neuro-060909-153138 CrossRefPubMedPubMedCentral

Bhattacharya A, Kaphzan H, Alvarez-Dieppa AC, Murphy JP, Pierre P, Klann E (2012) Genetic removal of p70 S6 kinase 1 corrects molecular, synaptic, and behavioral phenotypes in fragile × syndrome mice. Neuron 76:325–337. https://doi.org/10.1016/j.neuron.2012.07.022 CrossRefPubMedPubMedCentral

Bloch A, Probst A, Bissig H, Adams H, Tolnay M (2006) Alpha-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

Bohnen NI, Albin RL (2011) The cholinergic system and Parkinson disease. Behav Brain Res 221:564–573. https://doi.org/10.1016/j.bbr.2009.12.048 CrossRefPubMed

Boivin M, Willemsen R, Hukema RK, Sellier C (2017) Potential pathogenic mechanisms underlying Fragile × Tremor Ataxia Syndrome: RAN translation and/or RNA gain-of-function? Eur J Med Genet. https://doi.org/10.1016/j.ejmg.2017.11.001 CrossRefPubMed

10.

Bolam JP, Pissadaki EK (2012) Living on the edge with too many mouths to feed: why dopamine neurons die. Mov Disord 27:1478–1483. https://doi.org/10.1002/mds.25135 CrossRefPubMedPubMedCentral

11.

Braak H, Braak H, Del Tredici K, Del Tredici K (2009) Neuroanatomy and pathology of sporadic Parkinson’s disease. Adv Anat Embryol Cell Biol 201:1–119PubMed

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 24:197–211CrossRefPubMed

13.

Brager DH, Akhavan AR, Johnston D (2012) Impaired dendritic expression and plasticity of h-channels in the fmr1(−/y) mouse model of fragile × syndrome. Cell Rep 1:225–233. https://doi.org/10.1016/j.celrep.2012.02.002 CrossRefPubMedPubMedCentral

14.

Brichta L, Greengard P (2014) Molecular determinants of selective dopaminergic vulnerability in Parkinson’s disease: an update. Front Neuroanat 8:152. https://doi.org/10.3389/fnana.2014.00152 CrossRefPubMedPubMedCentral

15.

Brown MR, Kronengold J, Gazula V-R, Chen Y, Strumbos JG, Sigworth FJ, Navaratnam D, Kaczmarek LK (2010) Fragile × mental retardation protein controls gating of the sodium-activated potassium channel Slack. Nat Neurosci 13:819–821. https://doi.org/10.1038/nn.2563 CrossRefPubMedPubMedCentral

16.

Brown V, Jin P, Ceman S, Darnell JC, O’Donnell WT, Tenenbaum SA, Jin X, Feng Y, Wilkinson KD, Keene JD, Darnell RB, Warren ST (2001) Microarray identification of FMRP-associated brain mRNAs and altered mRNA translational profiles in fragile × syndrome. Cell 107:477–487CrossRefPubMed

17.

Bruch J, Xu H, De Andrade A, Höglinger G (2014) Mitochondrial complex 1 inhibition increases 4-repeat isoform tau by SRSF2 upregulation. PLoS One 9:e113070. https://doi.org/10.1371/journal.pone.0113070 CrossRefPubMedPubMedCentral

18.

Bruch J, Xu H, Rösler TW, De Andrade A, Kuhn P-H, Lichtenthaler SF, Arzberger T, Winklhofer KF, Müller U, Höglinger GU (2017) PERK activation mitigates tau pathology in vitro and in vivo. EMBO Mol Med 9:371–384. https://doi.org/10.15252/emmm.201606664 CrossRefPubMedPubMedCentral

19.

Carbone C, Costa A, Provensi G, Mannaioni G, Masi A (2017) The hyperpolarization-activated current determines synaptic excitability, calcium activity and specific viability of substantia nigra dopaminergic neurons. Front Cell Neurosci 11:251-14. https://doi.org/10.3389/fncel.2017.00187 CrossRef

20.

Ceman S, O’Donnell WT, Reed M, Patton S, Pohl J, Warren ST (2003) Phosphorylation influences the translation state of FMRP-associated polyribosomes. Hum Mol Genet 12:3295–3305. https://doi.org/10.1093/hmg/ddg350 CrossRefPubMed

21.

Ceravolo R, Antonini A, Volterrani D, Rossi C, Goldwurm S, Di Maria E, Kiferle L, Bonuccelli U, Murri L (2005) Dopamine transporter imaging study in parkinsonism occurring in fragile × premutation carriers. Neurology 65:1971–1973. https://doi.org/10.1212/01.wnl.0000188821.51055.52 CrossRefPubMed

22.

Chan CS, Guzman JN, Ilijic E, Mercer JN, Rick C, Tkatch T, Meredith GE, Surmeier DJ (2007) “Rejuvenation” protects neurons in mouse models of Parkinson’s disease. Nature 447:1081–1086. https://doi.org/10.1038/nature05865 CrossRefPubMed

23.

Chartier-Harlin M-C, Dachsel JC, Vilariño-Güell C, Lincoln SJ, Leprêtre F, Hulihan MM, Kachergus J, Milnerwood AJ, Tapia L, Song M-S, Le Rhun E, Mutez E, Larvor L, Duflot A, Vanbesien-Mailliot C, Kreisler A, Ross OA, Nishioka K, Soto-Ortolaza AI, Cobb SA, Melrose HL, Behrouz B, Keeling BH, Bacon JA, Hentati E, Williams L, Yanagiya A, Sonenberg N, Lockhart PJ, Zubair AC, Uitti RJ, Aasly JO, Krygowska-Wajs A, Opala G, Wszolek ZK, Frigerio R, Maraganore DM, Gosal D, Lynch T, Hutchinson M, Bentivoglio AR, Valente EM, Nichols WC, Pankratz N, Foroud T, Gibson RA, Hentati F, Dickson DW, Destée A, Farrer MJ (2011) Translation initiator EIF4G1 mutations in familial Parkinson disease. Am J Hum Genet 89:398–406. https://doi.org/10.1016/j.ajhg.2011.08.009 CrossRefPubMedPubMedCentral

24.

Chartier-Harlin MC, Chartier-Harlin M-C, Kachergus J, Kachergus J, Roumier C, Roumier C, Mouroux V, Mouroux V, Douay X, Douay X, Lincoln S, Lincoln S, Levecque C, Levecque C, Larvor L, Larvor L, Andrieux J, Andrieux J, Hulihan M, Hulihan M, Waucquier N, Waucquier N, Defebvre L, Defebvre L, Amouyel P, Amouyel P, Farrer M, Farrer M, Destee A, Destée A (2004) Alpha-synuclein locus duplication as a cause of familial Parkinson’s disease. Lancet 364:1167–1169. https://doi.org/10.1016/S0140-6736(04)17103-1 CrossRefPubMed

25.

Chen Y-C, Wu Y-R, Mesri M, Chen C-M (2016) Associations of matrix metalloproteinase-9 and tissue inhibitory factor-1 polymorphisms with Parkinson disease in Taiwan. Medicine (Baltimore) 95:e2672. https://doi.org/10.1097/MD.0000000000002672 CrossRef

26.

Cilia R, Kraff J, Canesi M, Pezzoli G, Goldwurm S, Amiri K, Tang H-T, Pan R, Hagerman PJ, Tassone F (2009) Screening for the presence of FMR1 premutation alleles in women with parkinsonism. Arch Neurol 66:244–249. https://doi.org/10.1001/archneurol.2008.548 CrossRefPubMed

27.

Contractor A, Klyachko VA, Portera-Cailliau C (2015) Altered neuronal and circuit excitability in fragile × syndrome. Neuron 87:699–715. https://doi.org/10.1016/j.neuron.2015.06.017 CrossRefPubMedPubMedCentral

28.

Costa A, Gao L, Carrillo F, Cáceres-Redondo MT, Carballo M, Díaz-Martín J, Gómez-Garre P, Sobrino F, Lucas M, López-Barneo J, Mir P, Pintado E (2011) Intermediate alleles at the FRAXA and FRAXE loci in Parkinson’s disease. Parkinsonism Relat Disord 17:281–284. https://doi.org/10.1016/j.parkreldis.2010.12.013 CrossRefPubMed

29.

Damier P, Hirsch EC, Agid Y, Graybiel AM (1999) The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson’s disease. Brain 122(Pt 8):1437–1448CrossRefPubMed

30.

Danesi C, Achuta VS, Corcoran P, Peteri U-K, Turconi G, Matsui N, Albayrak I, Rezov V, Isaksson A, Castrén ML (2018) Increased calcium influx through L-type calcium channels in human and mouse neural progenitors lacking fragile × mental retardation protein. Stem Cell Reports. https://doi.org/10.1016/j.stemcr.2018.11.003 CrossRefPubMedPubMedCentral

31.

Darnell JC, Van Driesche SJ, Zhang C, Hung KYS, Mele A, Fraser CE, Stone EF, Chen C, Fak JJ, Chi SW, Licatalosi DD, Richter JD, Darnell RB (2011) FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146:247–261. https://doi.org/10.1016/j.cell.2011.06.013 CrossRefPubMedPubMedCentral

32.

De Pablo-Fernandez E, Doherty KM, Holton JL, Revesz T, Djamshidian A, Limousin P, Bhatia KP, Warner TT, Lees AJ, Ling H (2015) Concomitant fragile X-associated tremor ataxia syndrome and Parkinson’s disease: a clinicopathological report of two cases. J Neurol Neurosurg Psychiatr 86:934–936. https://doi.org/10.1136/jnnp-2014-309460 CrossRef

33.

Del Tredici K, Braak H (2016) Review: sporadic Parkinson’s disease: development and distribution of α-synuclein pathology. Neuropathol Appl Neurobiol 42:33–50. https://doi.org/10.1111/nan.12298 CrossRefPubMed

34.

DelleDonne A, Klos KJ, Fujishiro H, Ahmed Z, Parisi JE, Josephs KA, Frigerio R, Burnett M, Wszolek ZK, Uitti RJ, Ahlskog JE, Dickson DW (2008) Incidental Lewy body disease and preclinical Parkinson disease. Arch Neurol 65:1074–1080. https://doi.org/10.1001/archneur.65.8.1074 CrossRefPubMed

35.

Deng P-Y, Rotman Z, Blundon JA, Cho Y, Cui J, Cavalli V, Zakharenko SS, Klyachko VA (2013) FMRP regulates neurotransmitter release and synaptic information transmission by modulating action potential duration via BK channels. Neuron 77:696–711. https://doi.org/10.1016/j.neuron.2012.12.018 CrossRefPubMedPubMedCentral

36.

Dijkstra AA, Voorn P, Berendse HW, Groenewegen HJ, Bank Netherlands Brain, Rozemuller AJM, van de Berg WDJ (2014) Stage-dependent nigral neuronal loss in incidental Lewy body and Parkinson’s disease. Mov Disord 29:1244–1251. https://doi.org/10.1002/mds.25952 CrossRefPubMed

37.

Dölen G, Osterweil E, Rao BSS, Smith GB, Auerbach BD, Chattarji S, Bear MF (2007) Correction of fragile × syndrome in mice. Neuron 56:955–962. https://doi.org/10.1016/j.neuron.2007.12.001 CrossRefPubMedPubMedCentral

38.

Dragicevic E, Schiemann J, Liss B (2015) Dopamine midbrain neurons in health and Parkinson’s disease: emerging roles of voltage-gated calcium channels and ATP-sensitive potassium channels. Neuroscience 284:798–814. https://doi.org/10.1016/j.neuroscience.2014.10.037 CrossRefPubMed

39.

Dury AY, El Fatimy R, Tremblay S, Rose TM, Côté J, De Koninck P, Khandjian EW (2013) Nuclear fragile × mental retardation protein is localized to cajal bodies. PLoS Genet 9:e1003890. https://doi.org/10.1371/journal.pgen.1003890 CrossRefPubMedPubMedCentral

40.

Feng Y, Gutekunst CA, Eberhart DE, Yi H, Warren ST, Hersch SM (1997) Fragile × mental retardation protein: nucleocytoplasmic shuttling and association with somatodendritic ribosomes. J Neurosci 17:1539–1547CrossRefPubMedPubMedCentral

41.

Ferron L, Nieto-Rostro M, Cassidy JS, Dolphin AC (2014) Fragile × mental retardation protein controls synaptic vesicle exocytosis by modulating N-type calcium channel density. Nat Commun 5:1–14. https://doi.org/10.1038/ncomms4628 CrossRef

42.

Ferron L, Nieto-Rostro M, Cassidy JS, Dolphin AC (2014) Fragile × mental retardation protein controls synaptic vesicle exocytosis by modulating N-type calcium channel density. Nat Commun 5:3628. https://doi.org/10.1038/ncomms4628 CrossRefPubMed

43.

Fu YH, Kuhl DP, Pizzuti A, Pieretti M, Sutcliffe JS, Richards S, Verkerk AJ, Holden JJ, Fenwick RG, Warren ST (1991) Variation of the CGG repeat at the fragile × site results in genetic instability: resolution of the Sherman paradox. Cell 67:1047–1058CrossRefPubMed

44.

Fujioka S, Sundal C, Strongosky AJ, Castanedes MC, Rademakers R, Ross OA, Vilariño-Güell C, Farrer MJ, Wszolek ZK, Dickson DW (2013) Sequence variants in eukaryotic translation initiation factor 4-gamma (eIF4G1) are associated with Lewy body dementia. Acta Neuropathol 125:425–438. https://doi.org/10.1007/s00401-012-1059-4 CrossRefPubMed

45.

Furic L, Rong L, Larsson O, Koumakpayi IH, Yoshida K, Brueschke A, Petroulakis E, Robichaud N, Pollak M, Gaboury LA, Pandolfi PP, Saad F, Sonenberg N (2010) eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression. Proc Natl Acad Sci USA 107:14134–14139. https://doi.org/10.1073/pnas.1005320107 CrossRefPubMedPubMedCentral

46.

Fussi N, Höllerhage M, Chakroun T, Nykänen N-P, Rösler TW, Koeglsperger T, Wurst W, Behrends C, Höglinger GU (2018) Exosomal secretion of α-synuclein as protective mechanism after upstream blockage of macroautophagy. Cell Death Dis 9:757. https://doi.org/10.1038/s41419-018-0816-2 CrossRefPubMedPubMedCentral

47.

Gehrke S, Wu Z, Klinkenberg M, Sun Y, Auburger G, Guo S, Lu B (2015) PINK1 and Parkin control localized translation of respiratory chain component mRNAs on mitochondria outer membrane. Cell Metab 21:95–108. https://doi.org/10.1016/j.cmet.2014.12.007 CrossRefPubMedPubMedCentral

48.

Giguère N, Burke Nanni S, Trudeau L-É (2018) On cell loss and selective vulnerability of neuronal populations in Parkinson’s disease. Front Neurol 9:455. https://doi.org/10.3389/fneur.2018.00455 CrossRefPubMedPubMedCentral

49.

Gkogkas CG, Khoutorsky A, Cao R, Jafarnejad SM, Prager-Khoutorsky M, Giannakas N, Kaminari A, Fragkouli A, Nader K, Price TJ, Konicek BW, Graff JR, Tzinia AK, Lacaille J-C, Sonenberg N (2014) Pharmacogenetic inhibition of eIF4E-dependent Mmp9 mRNA translation reverses fragile × syndrome-like phenotypes. Cell Rep 9:1742–1755. https://doi.org/10.1016/j.celrep.2014.10.064 CrossRefPubMedPubMedCentral

50.

Gkogkas CG, Khoutorsky A, Ran I, Rampakakis E, Nevarko T, Weatherill DB, Vasuta C, Yee S, Truitt M, Dallaire P, Major F, Lasko P, Ruggero D, Nader K, Lacaille J-C, Sonenberg N (2013) Autism-related deficits via dysregulated eIF4E-dependent translational control. Nature 493:371–377. https://doi.org/10.1038/nature11628 CrossRefPubMed

51.

Goedert M, Spillantini MG, Del Tredici K, Braak H (2013) 100 years of Lewy pathology. Nat Rev Neurol 9:13–24. https://doi.org/10.1038/nrneurol.2012.242 CrossRefPubMed

52.

Greene JG, Dingledine R, Greenamyre JT (2005) Gene expression profiling of rat midbrain dopamine neurons: implications for selective vulnerability in parkinsonism. Neurobiol Dis 18:19–31. https://doi.org/10.1016/j.nbd.2004.10.003 CrossRefPubMed

53.

Grigsby J (2016) The fragile × mental retardation 1 gene (FMR1): historical perspective, phenotypes, mechanism, pathology, and epidemiology. Clin Neuropsychol 30:815–833. https://doi.org/10.1080/13854046.2016.1184652 CrossRefPubMedPubMedCentral

54.

Grimm J, Mueller A, Hefti F, Rosenthal A (2004) Molecular basis for catecholaminergic neuron diversity. Proc Natl Acad Sci USA 101:13891–13896. https://doi.org/10.1073/pnas.0405340101 CrossRefPubMedPubMedCentral

55.

Gross C, Yao X, Pong DL, Jeromin A, Bassell GJ (2011) Fragile × mental retardation protein regulates protein expression and mRNA translation of the potassium channel Kv4.2. J Neurosci 31:5693–5698. https://doi.org/10.1523/JNEUROSCI.6661-10.2011 CrossRefPubMedPubMedCentral

56.

Guzman JN, Ilijic E, Yang B, Sanchez-Padilla J, Wokosin D, Galtieri D, Kondapalli J, Schumacker PT, Surmeier DJ (2018) Systemic isradipine treatment diminishes calcium-dependent mitochondrial oxidant stress. J Clin Invest 128:2266–2280. https://doi.org/10.1172/JCI95898 CrossRefPubMedPubMedCentral

57.

Guzman JN, Sanchez-Padilla J, Chan CS, Surmeier DJ (2009) Robust pacemaking in substantia nigra dopaminergic neurons. J Neurosci 29:11011–11019. https://doi.org/10.1523/JNEUROSCI.2519-09.2009 CrossRefPubMedPubMedCentral

58.

Guzman JN, Sanchez-Padilla J, Wokosin D, Kondapalli J, Ilijic E, Schumacker PT, Surmeier DJ (2010) Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1. Nature 468:696–700. https://doi.org/10.1038/nature09536 CrossRefPubMedPubMedCentral

59.

Hagerman PJ, Hagerman RJ (2015) Fragile X-associated tremor/ataxia syndrome. Ann N Y Acad Sci 1338:58–70. https://doi.org/10.1111/nyas.12693 CrossRefPubMedPubMedCentral

60.

Hagerman RJ, Hagerman P (2016) Fragile X-associated tremor/ataxia syndrome—features, mechanisms and management. Nat Rev Neurol 12:403–412. https://doi.org/10.1038/nrneurol.2016.82 CrossRefPubMed

61.

Hall DA, Berry-Kravis E, Jacquemont S, Rice CD, Cogswell J, Zhang L, Hagerman RJ, Hagerman PJ, Leehey MA (2005) Initial diagnoses given to persons with the fragile × associated tremor/ataxia syndrome (FXTAS). Neurology 65:299–301. https://doi.org/10.1212/01.wnl.0000168900.86323.9c CrossRefPubMed

62.

Hall DA, Howard K, Hagerman R, Leehey MA (2009) Parkinsonism in FMR1 premutation carriers may be indistinguishable from Parkinson disease. Parkinsonism Relat Disord 15:156–159. https://doi.org/10.1016/j.parkreldis.2008.04.037 CrossRefPubMed

63.

Hall DA, Jennings D, Seibyl J, Tassone F, Marek K (2010) FMR1 gene expansion and scans without evidence of dopaminergic deficits in parkinsonism patients. Parkinsonism Relat Disord 16:608–611. https://doi.org/10.1016/j.parkreldis.2010.07.006 CrossRefPubMedPubMedCentral

64.

Halliday GM, Blumbergs PC, Cotton RG, Blessing WW, Geffen LB (1990) Loss of brainstem serotonin- and substance P-containing neurons in Parkinson’s disease. Brain Res 510:104–107. https://doi.org/10.1016/0006-8993(90)90733-r CrossRefPubMed

65.

Halliday GM, Li YW, Blumbergs PC, Joh TH, Cotton RG, Howe PR, Blessing WW, Geffen LB (1990) Neuropathology of immunohistochemically identified brainstem neurons in Parkinson’s disease. Ann Neurol 27:373–385. https://doi.org/10.1002/ana.410270405 CrossRefPubMed

66.

Halliday GM, McRitchie DA, Cartwright H, Pamphlett R, Hely MA, Morris JG (1996) Midbrain neuropathology in idiopathic Parkinson’s disease and diffuse Lewy body disease. J Clin Neurosci 3:52–60CrossRefPubMed

67.

Healy DG, Bressman S, Dickson J, Silveira-Moriyama L, Schneider SA, Sullivan SSO, Massey L, Shaw K, Bhatia KP, Bomanji J, Wood NW, Lees AJ (2009) Evidence for pre and postsynaptic nigrostriatal dysfunction in the fragile × tremor-ataxia syndrome. Mov Disord 24:1245–1247. https://doi.org/10.1002/mds.22267 CrossRefPubMed

68.

Hollerhage M, Goebel JN, de Andrade A, Hildebrandt T, Dolga A, Culmsee C, Oertel WH, Hengerer B, Hoglinger GU (2014) Trifluoperazine rescues human dopaminergic cells from wild-type alpha-synuclein-induced toxicity. Neurobiol Aging 35:1700–1711. https://doi.org/10.1016/j.neurobiolaging.2014.01.027 CrossRefPubMed

69.

Hoozemans JJM, van Haastert ES, Eikelenboom P, de Vos RAI, Rozemuller JM, Scheper W (2007) Activation of the unfolded protein response in Parkinson’s disease. Biochem Biophys Res Commun 354:707–711. https://doi.org/10.1016/j.bbrc.2007.01.043 CrossRefPubMed

70.

Hornykiewicz O (2002) Dopamine miracle: from brain homogenate to dopamine replacement. Mov Disord 17:501–508. https://doi.org/10.1002/mds.10115 CrossRefPubMed

71.

Hou L, Antion MD, Hu D, Spencer CM, Paylor R, Klann E (2006) Dynamic translational and proteasomal regulation of fragile × mental retardation protein controls mGluR-dependent long-term depression. Neuron 51:441–454. https://doi.org/10.1016/j.neuron.2006.07.005 CrossRefPubMed

72.

Huntley GW (2012) Synaptic circuit remodelling by matrix metalloproteinases in health and disease. Nat Rev Neurosci 13:743–757. https://doi.org/10.1038/nrn3320 CrossRefPubMedPubMedCentral

73.

Imai Y, Gehrke S, Wang H-Q, Takahashi R, Hasegawa K, Oota E, Lu B (2008) Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila. EMBO J 27:2432–2443. https://doi.org/10.1038/emboj.2008.163 CrossRefPubMedPubMedCentral

74.

Janusz A, Milek J, Perycz M, Pacini L, Bagni C, Kaczmarek L, Dziembowska M (2013) The Fragile × mental retardation protein regulates matrix metalloproteinase 9 mRNA at synapses. J Neurosci 33:18234–18241. https://doi.org/10.1523/JNEUROSCI.2207-13.2013 CrossRefPubMedPubMedCentral

75.

Khaliq ZM, Bean BP (2010) Pacemaking in dopaminergic ventral tegmental area neurons: depolarizing drive from background and voltage-dependent sodium conductances. J Neurosci 30:7401–7413. https://doi.org/10.1523/JNEUROSCI.0143-10.2010 CrossRefPubMedPubMedCentral

76.

Khandjian EW, Corbin F, Woerly S, Rousseau F (1996) The fragile × mental retardation protein is associated with ribosomes. Nat Genet 12:91–93. https://doi.org/10.1038/ng0196-91 CrossRefPubMed

77.

Kremer HP, Bots GT (1993) Lewy bodies in the lateral hypothalamus: do they imply neuronal loss? Mov Disord 8:315–320. https://doi.org/10.1002/mds.870080310 CrossRefPubMed

78.

Krüger R, Kuhn W, Müller T, Woitalla D, Graeber M, Kösel S, Przuntek H, Epplen JT, Schöls L, Riess O (1998) Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet 18:106–108. https://doi.org/10.1038/ng0298-106 CrossRefPubMed

79.

Kthiri F, Gautier V, Le H-T, Prère M-F, Fayet O, Malki A, Landoulsi A, Richarme G (2010) Translational defects in a mutant deficient in YajL, the bacterial homolog of the parkinsonism-associated protein DJ-1. J Bacteriol 192:6302–6306. https://doi.org/10.1128/JB.01077-10 CrossRefPubMedPubMedCentral

80.

Lee HY, Ge W-P, Huang W, He Y, Wang GX, Rowson-Baldwin A, Smith SJ, Jan YN, Jan LY (2011) Bidirectional regulation of dendritic voltage-gated potassium channels by the fragile × mental retardation protein. Neuron 72:630–642. https://doi.org/10.1016/j.neuron.2011.09.033 CrossRefPubMedPubMedCentral

81.

Levin J, Giese A, Boetzel K, Israel L, Högen T, Nübling G, Kretzschmar H, Lorenzl S (2009) Increased alpha-synuclein aggregation following limited cleavage by certain matrix metalloproteinases. Exp Neurol 215:201–208. https://doi.org/10.1016/j.expneurol.2008.10.010 CrossRefPubMed

82.

Lin W, Wadlington NL, Chen L, Zhuang X, Brorson JR, Kang UJ (2014) Loss of PINK1 attenuates HIF-1α induction by preventing 4E-BP1-dependent switch in protein translation under hypoxia. J Neurosci 34:3079–3089. https://doi.org/10.1523/JNEUROSCI.2286-13.2014 CrossRefPubMedPubMedCentral

83.

Liss B, Haeckel O, Wildmann J, Miki T, Seino S, Roeper J (2005) K-ATP channels promote the differential degeneration of dopaminergic midbrain neurons. Nat Neurosci 8:1742–1751. https://doi.org/10.1038/nn1570 CrossRefPubMed

84.

Liss B, Roeper J (2010) Ion channels and regulation of dopamine neuron activity. Sudha M Dopamine handbook. Oxford University Press, Oxford, pp 1–21

85.

Liu S, Lu B (2010) Reduction of protein translation and activation of autophagy protect against PINK1 pathogenesis in Drosophila melanogaster. PLoS Genet 6:e1001237. https://doi.org/10.1371/journal.pgen.1001237 CrossRefPubMedPubMedCentral

86.

Martin I, Kim JW, Lee BD, Kang HC, Xu J-C, Jia H, Stankowski J, Kim M-S, Zhong J, Kumar M, Andrabi SA, Xiong Y, Dickson DW, Wszolek ZK, Pandey A, Dawson TM, Dawson VL (2014) Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson’s disease. Cell 157:472–485. https://doi.org/10.1016/j.cell.2014.01.064 CrossRefPubMedPubMedCentral

87.

Masi A, Narducci R, Resta F, Carbone C, Kobayashi K, Mannaioni G (2015) Differential contribution of Ih to the integration of excitatory synaptic inputs in substantia nigra pars compacta and ventral tegmental area dopaminergic neurons. Eur J Neurosci 42:2699–2706. https://doi.org/10.1111/ejn.13066 CrossRefPubMed

88.

Miyashiro KY, Beckel-Mitchener A, Purk TP, Becker KG, Barret T, Liu L, Carbonetto S, Weiler IJ, Greenough WT, Eberwine J (2003) RNA cargoes associating with FMRP reveal deficits in cellular functioning in Fmr1 null mice. Neuron 37:417–431CrossRefPubMed

89.

Morris TJ, Butcher LM, Feber A, Teschendorff AE, Chakravarthy AR, Wojdacz TK, Beck S (2014) ChAMP: 450k chip analysis methylation pipeline. Bioinformatics 30:428–430. https://doi.org/10.1093/bioinformatics/btt684 CrossRefPubMed

90.

Mutez E, Nkiliza A, Belarbi K, de Broucker A, Vanbesien-Mailliot C, Bleuse S, Duflot A, Comptdaer T, Semaille P, Blervaque R, Hot D, Leprêtre F, Figeac M, Destée A, Chartier-Harlin M-C (2014) Involvement of the immune system, endocytosis and EIF2 signaling in both genetically determined and sporadic forms of Parkinson’s disease. Neurobiol Dis 63:165–170. https://doi.org/10.1016/j.nbd.2013.11.007 CrossRefPubMed

91.

Nalls MA, Pankratz N, Lill CM, Do CB, Hernandez DG, Saad M, DeStefano AL, Kara E, Bras J, Sharma M, Schulte C, Keller MF, Arepalli S, Letson C, Edsall C, Stefansson H, Liu X, Pliner H, Lee JH, Cheng R, Ikram MA, Ioannidis JPA, Hadjigeorgiou GM, Bis JC, Martinez M, Perlmutter JS, Goate A, Marder K, Fiske B, Sutherland M, Xiromerisiou G, Myers RH, Clark LN, Stefansson K, Hardy JA, Heutink P, Chen H, Wood NW, Houlden H, Payami H, Brice A, Scott WK, Gasser T, Bertram L, Eriksson N, Foroud T, Singleton AB, International Parkinson’s Disease Genomics Consortium (IPDGC), Parkinson’s Study Group (PSG) Parkinson’s Research: The Organized GENetics Initiative (PROGENI), 23andMe, GenePD, NeuroGenetics Research Consortium (NGRC), Hussman Institute of Human Genomics (HIHG), Ashkenazi Jewish Dataset Investigator, Cohorts for Health and Aging Research in Genetic Epidemiology (CHARGE), North American Brain Expression Consortium (NABEC), United Kingdom Brain Expression Consortium (UKBEC), Greek Parkinson’s Disease Consortium, Alzheimer Genetic Analysis Group (2014) Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat Genet 46:989–993. https://doi.org/10.1038/ng.3043 CrossRefPubMedPubMedCentral

92.

Napoli I, Mercaldo V, Boyl PP, Eleuteri B, Zalfa F, De Rubeis S, Di Marino D, Mohr E, Massimi M, Falconi M, Witke W, Costa-Mattioli M, Sonenberg N, Achsel T, Bagni C (2008) The fragile × syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP. Cell 134:1042–1054. https://doi.org/10.1016/j.cell.2008.07.031 CrossRefPubMed

93.

Niu Y-Q, Yang J-C, Hall DA, Leehey MA, Tassone F, Olichney JM, Hagerman RJ, Zhang L (2014) Parkinsonism in fragile X-associated tremor/ataxia syndrome (FXTAS): revisited. Parkinsonism Relat Disord 20:456–459. https://doi.org/10.1016/j.parkreldis.2014.01.006 CrossRefPubMedPubMedCentral

94.

Nordlund J, Bäcklin CL, Wahlberg P, Busche S, Berglund EC, Eloranta M-L, Flaegstad T, Forestier E, Frost B-M, Harila-Saari A, Heyman M, Jónsson OG, Larsson R, Palle J, Rönnblom L, Schmiegelow K, Sinnett D, Söderhäll S, Pastinen T, Gustafsson MG, Lönnerholm G, Syvänen A-C (2013) Genome-wide signatures of differential DNA methylation in pediatric acute lymphoblastic leukemia. Genome Biol 14:r105. https://doi.org/10.1186/gb-2013-14-9-r105 CrossRefPubMedPubMedCentral

95.

Osterweil EK, Chuang S-C, Chubykin AA, Sidorov M, Bianchi R, Wong RKS, Bear MF (2013) Lovastatin corrects excess protein synthesis and prevents epileptogenesis in a mouse model of fragile × syndrome. Neuron 77:243–250. https://doi.org/10.1016/j.neuron.2012.01.034 CrossRefPubMedPubMedCentral

96.

Osterweil EK, Krueger DD, Reinhold K, Bear MF (2010) Hypersensitivity to mGluR5 and ERK1/2 leads to excessive protein synthesis in the hippocampus of a mouse model of fragile × syndrome. J Neurosci 30:15616–15627. https://doi.org/10.1523/JNEUROSCI.3888-10.2010 CrossRefPubMedPubMedCentral

97.

Ostrerova N, Petrucelli L, Farrer M, Mehta N, Choi P, Hardy J, Wolozin B (1999) alpha-Synuclein shares physical and functional homology with 14-3-3 proteins. J Neurosci 19:5782–5791CrossRefPubMedPubMedCentral

98.

Ottone C, Galasso A, Gemei M, Pisa V, Gigliotti S, Piccioni F, Graziani F, Verrotti di Pianella A (2011) Diminution of eIF4E activity suppresses parkin mutant phenotypes. Gene 470:12–19. https://doi.org/10.1016/j.gene.2010.09.003 CrossRefPubMed

99.

Pacelli C, Giguère N, Bourque M-J, Lévesque M, Slack RS, Trudeau L-É (2015) Elevated mitochondrial bioenergetics and axonal arborization size are key contributors to the vulnerability of dopamine neurons. Curr Biol 25:2349–2360. https://doi.org/10.1016/j.cub.2015.07.050 CrossRefPubMed

100.

Pérez-Villalba A, Sirerol-Piquer MS, Belenguer G, Soriano-Cantón R, Muñoz-Manchado AB, Villadiego J, Alarcón-Arís D, Soria FN, Dehay B, Bezard E, Vila M, Bortolozzi A, Toledo-Aral JJ, Pérez-Sánchez F, Fariñas I (2018) Synaptic regulator α-synuclein in dopaminergic fibers is essentially required for the maintenance of subependymal neural stem cells. J Neurosci 38:814–825. https://doi.org/10.1523/JNEUROSCI.2276-17.2017 CrossRefPubMedPubMedCentral

101.

Philippart F, Destreel G, Merino-Sepulveda P, Henny P, Engel D, Seutin V (2016) Differential somatic Ca²⁺ channel profile in midbrain dopaminergic neurons. J Neurosci 36:7234–7245. https://doi.org/10.1523/JNEUROSCI.0459-16.2016 CrossRefPubMedPubMedCentral

102.

Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047CrossRefPubMed

103.

Qin M (2005) Postadolescent changes in regional cerebral protein synthesis: an in vivo study in the Fmr1 null mouse. J Neurosci 25:5087–5095. https://doi.org/10.1523/JNEUROSCI.0093-05.2005 CrossRefPubMedPubMedCentral

104.

Qin M, Schmidt KC, Zametkin AJ, Bishu S, Horowitz LM, Burlin TV, Xia Z, Huang T, Quezado ZM, Smith CB (2013) Altered cerebral protein synthesis in fragile × syndrome: studies in human subjects and knockout mice. J Cereb Blood Flow Metab 33:499–507. https://doi.org/10.1038/jcbfm.2012.205 CrossRefPubMedPubMedCentral

105.

Reyniers L, Del Giudice MG, Civiero L, Belluzzi E, Lobbestael E, Beilina A, Arrigoni G, Derua R, Waelkens E, Li Y, Crosio C, Iaccarino C, Cookson MR, Baekelandt V, Greggio E, Taymans J-M (2014) Differential protein-protein interactions of LRRK1 and LRRK2 indicate roles in distinct cellular signaling pathways. J Neurochem 131:239–250. https://doi.org/10.1111/jnc.12798 CrossRefPubMedPubMedCentral

106.

Richter JD, Bassell GJ, Klann E (2015) Dysregulation and restoration of translational homeostasis in fragile × syndrome. Nat Rev Neurosci 16:595–605. https://doi.org/10.1038/nrn4001 CrossRefPubMedPubMedCentral

107.

Riley BE, Gardai SJ, Emig-Agius D, Bessarabova M, Ivliev AE, Schüle B, Schüle B, Alexander J, Wallace W, Halliday GM, Langston JW, Braxton S, Yednock T, Shaler T, Johnston JA (2014) Systems-based analyses of brain regions functionally impacted in Parkinson’s disease reveals underlying causal mechanisms. PLoS One 9:e102909. https://doi.org/10.1371/journal.pone.0102909 CrossRefPubMedPubMedCentral

108.

Ronesi JA, Collins KA, Hays SA, Tsai N-P, Guo W, Birnbaum SG, Hu J-H, Worley PF, Gibson JR, Huber KM (2012) Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile × syndrome. Nat Neurosci 15:431. https://doi.org/10.1038/nn.3033 CrossRefPubMedPubMedCentral

109.

Routh BN, Johnston D, Brager DH (2013) Loss of functional A-type potassium channels in the dendrites of CA1 pyramidal neurons from a mouse model of fragile × syndrome. J Neurosci 33:19442–19450. https://doi.org/10.1523/JNEUROSCI.3256-13.2013 CrossRefPubMedPubMedCentral

110.

Scaglione C, Ginestroni A, Vella A, Dotti MT, Nave RD, Rizzo G, De Cristofaro MT, De Stefano N, Piacentini S, Martinelli P, Mascalchi M (2008) MRI and SPECT of midbrain and striatal degeneration in fragile X-associated tremor/ataxia syndrome. J Neurol 255:144–146. https://doi.org/10.1007/s00415-007-0711-8 CrossRefPubMed

111.

Schmidt EK, Clavarino G, Ceppi M, Pierre P (2009) SUnSET, a nonradioactive method to monitor protein synthesis. Nat Methods 6:275–277. https://doi.org/10.1038/nmeth.1314 CrossRefPubMed

112.

Scholz D, Pöltl D, Genewsky A, Weng M, Waldmann T, Schildknecht S, Leist M (2011) Rapid, complete and large-scale generation of post-mitotic neurons from the human LUHMES cell line. J Neurochem 119:957–971. https://doi.org/10.1111/j.1471-4159.2011.07255.x CrossRefPubMed

113.

Schulz J, Pagano G, Fernández Bonfante JA, Wilson H, Politis M (2018) Nucleus basalis of Meynert degeneration precedes and predicts cognitive impairment in Parkinson’s disease. Brain 141:1501–1516. https://doi.org/10.1093/brain/awy072 CrossRefPubMedPubMedCentral

114.

Sellier C, Buijsen RAM, He F, Natla S, Jung L, Tropel P, Gaucherot A, Jacobs H, Meziane H, Vincent A, Champy M-F, Sorg T, Pavlovic G, Wattenhofer-Donze M, Birling M-C, Oulad-Abdelghani M, Eberling P, Ruffenach F, Joint M, Anheim M, Martinez-Cerdeno V, Tassone F, Willemsen R, Hukema RK, Viville S, Martinat C, Todd PK, Charlet-Berguerand N (2017) Translation of expanded CGG repeats into FMRpolyG is pathogenic and may contribute to fragile × tremor ataxia syndrome. Neuron 93:331–347. https://doi.org/10.1016/j.neuron.2016.12.016 CrossRefPubMedPubMedCentral

115.

Sgobio C, Kupferschmidt DA, Cui G, Sun L, Li Z, Cai H, Lovinger DM (2014) Optogenetic measurement of presynaptic calcium transients using conditional genetically encoded calcium indicator expression in dopaminergic neurons. PLoS One 9:e111749. https://doi.org/10.1371/journal.pone.0111749 CrossRefPubMedPubMedCentral

116.

Sharma A, Hoeffer CA, Takayasu Y, Miyawaki T, McBride SM, Klann E, Zukin RS (2010) Dysregulation of mTOR signaling in fragile × syndrome. J Neurosci 30:694–702. https://doi.org/10.1523/JNEUROSCI.3696-09.2010 CrossRefPubMedPubMedCentral

117.

Sidhu H, Dansie LE, Hickmott PW, Ethell DW, Ethell IM (2014) Genetic removal of matrix metalloproteinase 9 rescues the symptoms of fragile × syndrome in a mouse model. J Neurosci 34:9867–9879. https://doi.org/10.1523/JNEUROSCI.1162-14.2014 CrossRefPubMedPubMedCentral

118.

Siller SS, Broadie K (2011) Neural circuit architecture defects in a Drosophila model of Fragile × syndrome are alleviated by minocycline treatment and genetic removal of matrix metalloproteinase. Dis Model Mech 4:673–685. https://doi.org/10.1242/dmm.008045 CrossRefPubMedPubMedCentral

119.

Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K (2003) alpha-Synuclein locus triplication causes Parkinson’s disease. Science 302:841. https://doi.org/10.1126/science.1090278 CrossRefPubMed

120.

Siomi H, Siomi MC, Nussbaum RL, Dreyfuss G (1993) The protein product of the fragile × gene, FMR1, has characteristics of an RNA-binding protein. Cell 74:291–298CrossRefPubMed

121.

Smyth GK (2004) Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 3:3–25. https://doi.org/10.2202/1544-6115.1027 CrossRef

122.

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

123.

Stefani G, Fraser CE, Darnell JC, Darnell RB (2004) Fragile × mental retardation protein is associated with translating polyribosomes in neuronal cells. J Neurosci 24:7272–7276. https://doi.org/10.1523/JNEUROSCI.2306-04.2004 CrossRefPubMedPubMedCentral

124.

Surmeier DJ, Obeso JA, Halliday GM (2017) Selective neuronal vulnerability in Parkinson disease. Nat Rev Neurosci 18:101–113. https://doi.org/10.1038/nrn.2016.178 CrossRefPubMedPubMedCentral

125.

Taha MS, Nouri K, Milroy LG, Moll JM, Herrmann C, Brunsveld L, Piekorz RP, Ahmadian MR (2014) Subcellular fractionation and localization studies reveal a direct interaction of the fragile × mental retardation protein (FMRP) with nucleolin. PLoS One 9:e91465. https://doi.org/10.1371/journal.pone.0091465 CrossRefPubMedPubMedCentral

126.

Tain LS, Mortiboys H, Tao RN, Ziviani E, Bandmann O, Whitworth AJ (2009) Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss. Nat Neurosci 12:1129–1135. https://doi.org/10.1038/nn.2372 CrossRefPubMedPubMedCentral

127.

Tamanini F, Meijer N, Verheij C, Willems PJ, Galjaard H, Oostra BA, Hoogeveen AT (1996) FMRP is associated to the ribosomes via RNA. Hum Mol Genet 5:809–813CrossRefPubMed

128.

Teschendorff AE, Marabita F, Lechner M, Bartlett T, Tegner J, Gomez-Cabrero D, Beck S (2013) A beta-mixture quantile normalization method for correcting probe design bias in Illumina Infinium 450k DNA methylation data. Bioinformatics 29:189–196. https://doi.org/10.1093/bioinformatics/bts680 CrossRefPubMed

129.

Thannickal TC, Lai Y-Y, Siegel JM (2007) Hypocretin (orexin) cell loss in Parkinson’s disease. Brain 130:1586–1595. https://doi.org/10.1093/brain/awm097 CrossRefPubMed

130.

Tian Y, Morris TJ, Webster AP, Yang Z, Beck S, Feber A, Teschendorff AE (2017) ChAMP: updated methylation analysis pipeline for Illumina BeadChips. Bioinformatics 33:3982–3984. https://doi.org/10.1093/bioinformatics/btx513 CrossRefPubMedPubMedCentral

131.

Udagawa T, Farny NG, Jakovcevski M, Kaphzan H, Alarcon JM, Anilkumar S, Ivshina M, Hurt JA, Nagaoka K, Nalavadi VC, Lorenz LJ, Bassell GJ, Akbarian S, Chattarji S, Klann E, Richter JD (2013) Genetic and acute CPEB1 depletion ameliorate fragile × pathophysiology. Nat Med 19:1473–1477. https://doi.org/10.1038/nm.3353 CrossRefPubMedPubMedCentral

132.

Verkerk AJ, Pieretti M, Sutcliffe JS, Fu YH, Kuhl DP, Pizzuti A, Reiner O, Richards S, Victoria MF, Zhang FP (1991) Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile × syndrome. Cell 65:905–914CrossRefPubMed

133.

Volpicelli-Daley LA, Kirik D, Stoyka LE, Standaert DG, Harms AS (2016) How can rAAV-α-synuclein and the fibril α-synuclein models advance our understanding of Parkinson’s disease? J Neurochem 139(Suppl 1):131–155. https://doi.org/10.1111/jnc.13627 CrossRefPubMedPubMedCentral

134.

Wang G, Achim CL, Hamilton RL, Wiley CA, Soontornniyomkij V (1999) Tyramide signal amplification method in multiple-label immunofluorescence confocal microscopy. Methods 18:459–464. https://doi.org/10.1006/meth.1999.0813 CrossRefPubMed

135.

Wang H, Morishita Y, Miura D, Naranjo JR, Kida S, Zhuo M (2012) Roles of CREB in the regulation of FMRP by group I metabotropic glutamate receptors in cingulate cortex. Mol Brain 5:27. https://doi.org/10.1186/1756-6606-5-27 CrossRefPubMedPubMedCentral

136.

Waskiewicz AJ, Flynn A, Proud CG, Cooper JA (1997) Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2. EMBO J 16:1909–1920. https://doi.org/10.1093/emboj/16.8.1909 CrossRefPubMedPubMedCentral

137.

Waskiewicz AJ, Johnson JC, Penn B, Mahalingam M, Kimball SR, Cooper JA (1999) Phosphorylation of the cap-binding protein eukaryotic translation initiation factor 4E by protein kinase Mnk1 in vivo. Mol Cell Biol 19:1871–1880CrossRefPubMedPubMedCentral

138.

Winslow AR, Chen C-W, Corrochano S, Acevedo-Arozena A, Gordon DE, Peden AA, Lichtenberg M, Menzies FM, Ravikumar B, Imarisio S, Brown S, O’Kane CJ, Rubinsztein DC (2010) α-Synuclein impairs macroautophagy: implications for Parkinson’s disease. J Cell Biol 190:1023–1037. https://doi.org/10.1083/jcb.201003122 CrossRefPubMedPubMedCentral

139.

Yorgason JT, España RA, Jones SR (2011) Demon voltammetry and analysis software: analysis of cocaine-induced alterations in dopamine signaling using multiple kinetic measures. J Neurosci Methods 202:158–164. https://doi.org/10.1016/j.jneumeth.2011.03.001 CrossRefPubMedPubMedCentral

140.

Yu S, Pritchard M, Kremer E, Lynch M, Nancarrow J, Baker E, Holman K, Mulley JC, Warren ST, Schlessinger D (1991) Fragile × genotype characterized by an unstable region of DNA. Science 252:1179–1181CrossRefPubMed

141.

Zhang Y, Bonnan A, Bony G, Ferezou I, Pietropaolo S, Ginger M, Sans N, Rossier J, Oostra B, LeMasson G, Frick A (2014) Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1(−/y) mice. Nat Neurosci 17:1701–1709. https://doi.org/10.1038/nn.3864 CrossRefPubMed

142.

Zhou W, Laird PW, Shen H (2017) Comprehensive characterization, annotation and innovative use of Infinium DNA methylation BeadChip probes. Nucleic Acids Res 45:e22. https://doi.org/10.1093/nar/gkw967 CrossRefPubMed

143.

(1994) Fmr1 knockout mice: a model to study fragile × mental retardation. The Dutch-Belgian fragile × consortium. Cell 78:23–33

Title: Loss of fragile X mental retardation protein precedes Lewy pathology in Parkinson’s disease
Authors: Yi Tan
Carmelo Sgobio
Thomas Arzberger
Felix Machleid
Qilin Tang
Elisabeth Findeis
Jorg Tost
Tasnim Chakroun
Pan Gao
Mathias Höllerhage
Kai Bötzel
Jochen Herms
Günter Höglinger
Thomas Koeglsperger
Publication date: 01-02-2020
Publisher: Springer Berlin Heidelberg
Keywords: Disorders of Intellectual Development
Intellectual Disability
Parkinson's Disease
Published in: Acta Neuropathologica / Issue 2/2020
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-019-02099-5

At a glance: The STEP trials

Springer Medicine

Loss of fragile X mental retardation protein precedes Lewy pathology in Parkinson’s disease

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2020

The active contribution of OPCs to neuroinflammation is mediated by LRP1

Molecular characterization of histopathological ependymoma variants

Structural and functional conservation of non-lumenized lymphatic endothelial cells in the mammalian leptomeninges

Overlapping genetic architecture between Parkinson disease and melanoma

The histomolecular criteria established for adult anaplastic pilocytic astrocytoma are not applicable to the pediatric population

Correction to: Risk-adapted therapy and biological heterogeneity in pineoblastoma: integrated clinico-pathological analysis from the prospective, multi-center SJMB03 and SJYC07 trials