Acta Neuropathologica

, Volume 123, Issue 6, pp 825–839 | Cite as

Pattern of ubiquilin pathology in ALS and FTLD indicates presence of C9ORF72 hexanucleotide expansion

  • Johannes Brettschneider
  • Vivianna M. Van Deerlin
  • John L. Robinson
  • Linda Kwong
  • Edward B. Lee
  • Yousuf O. Ali
  • Nathaniel Safren
  • Mervyn J. Monteiro
  • Jon B. Toledo
  • Lauren Elman
  • Leo McCluskey
  • David J. Irwin
  • Murray Grossman
  • Laura Molina-Porcel
  • Virginia M.-Y. Lee
  • John Q. Trojanowski
Original Paper

Abstract

C9ORF72-hexanucleotide repeat expansions and ubiquilin-2 (UBQLN2) mutations are recently identified genetic markers in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). We investigate the relationship between C9ORF72 expansions and the clinical phenotype and neuropathology of ALS and FTLD. Genetic analysis and immunohistochemistry (IHC) were performed on autopsy-confirmed ALS (N = 75), FTLD-TDP (N = 30), AD (N = 14), and controls (N = 11). IHC for neurodegenerative disease pathology consisted of C9ORF72, UBQLN, p62, and TDP-43. A C9ORF72 expansion was identified in 19.4 % of ALS and 31 % of FTLD-TDP cases. ALS cases with C9ORF72 expansions frequently showed a bulbar onset of disease (57 %) and more rapid disease progression to death compared to non-expansion cases. Staining with C9ORF72 antibodies did not yield specific pathology. UBQLN pathology showed a highly distinct pattern in ALS and FTLD-TDP cases with the C9ORF72 expansion, with UBQLN-positive cytoplasmic inclusions in the cerebellar granular layer and extensive UBQLN-positive aggregates and dystrophic neurites in the hippocampal molecular layer and CA regions. These UBQLN pathologies were sufficiently unique to allow correct prediction of cases that were later confirmed to have C9ORF72 expansions by genetic analysis. UBQLN pathology partially co-localized with p62, and to a minor extent with TDP-43 positive dystrophic neurites and spinal cord skein-like inclusions. Our data indicate a pathophysiological link between C9ORF72 expansions and UBQLN proteins in ALS and FTLD-TDP that is associated with a highly characteristic pattern of UBQLN pathology. Our study indicates that this pathology is associated with alterations in clinical phenotype, and suggests that the presence of C9ORF72 repeat expansions may indicate a worse prognosis in ALS.

Keywords

Amyotrophic lateral sclerosis Frontotemporal lobar degeneration C9ORF72 UBQLN2 UBQLN1 

Supplementary material

401_2012_970_MOESM1_ESM.tif (4 mb)
Supplementary figure 1 CORF72 antibody detects both short and long isoforms of the translated protein. 293T cells were transfected with vectors overexpressing either GFP or the C9ORF72 long (DDK-Myc-T1) or short isoforms (DDK-Myc-T2) tagged at the C-terminal with DDK- and myc-tags, using Lipofectamine-2000 (Invitrogen). At 48 h post-transfection, the cells were lysed with RIPA buffer and proteins concentrations were measured using the Bradford protein assay (BioRad). Sample lysates were resolved by SDS-PAGE and probed with: anti-DDK 1:2000 (Origene Technologies) or anti-C9ORF72 1:1000 (Sigma). Western blot analysis was performed by incubating with the infrared dye-conjugated secondary antibodies, IR700 and IR800 (LI-COR Biosciences) for 1 h at room temperature; blots were imaged and processed on an Odyssey® Infrared Imaging System. The DDK antibody (left panel, red) detected the overexpressed proteins: around 56 kDa for the long isoform and around 26 kDa for the short isoform. The commercial C9ORF72 antibody (middle panel, green) was able to detect both the overexpressed isoforms as well (see overlap between the 700 and 800 channels in right panel). In addition, the commercial antibody was also able to detect the endogenous C9ORF72 long isoform, which is abundantly present in 293T cells. (TIFF 4053 kb)
401_2012_970_MOESM2_ESM.jpg (414 kb)
Supplementary figure 2 C9ORF72 pathology in ALS and CTRL as seen by IHC. Coarse punctate staining of synaptic terminals in the CA4 region of the hippocampus (a, shown in higher resolution in b and c) that were observed in ALS, FTLD-TDP and CTRL without any difference in extent or regional distribution between the groups. Scale bars: a 200 µm, b, c 20 µm. (JPEG 414 kb)
401_2012_970_MOESM3_ESM.tif (864 kb)
Supplementary figure 3 Testing UBQLN antibody specificity. (a-c) Either human embryonic 293T or murine 3T3 fibroblasts were transfected with GFP-UBQLN1 or control GFP vectors, using Lipofectamine-2000 (Invitrogen). 293T cells were used to test if the antibodies could detect endogenous human UBQLN proteins; mouse 3T3 cells allowed for testing the specificity of the antibodies for human, and not endogenous mouse UBQLN proteins. At 48 h post-transfection, the cells were lysed with RIPA buffer and proteins concentrations were measured using the Bradford protein assay (BioRad). Both sample lysates and purified recombinant GST-tagged UBQLN1 protein were resolved by SDS-PAGE and probed with: anti-UBQLN1, 1:500 or anti-UBQLN2 1:1000 (Abnova, Walnut, CA). Western blot analysis was performed by incubating with the infrared dye-conjugated secondary antibodies, IR700 and IR800 (LI-COR Biosciences) for 1 h at room temperature; blots were imaged and processed on an Odyssey® Infrared Imaging System. The UBQLN1 antibody (a) specifically detected the recombinant GST-UBQLN1 (~98 kDa) as well as GFP-UBQLN1, and endogenous human UBQLN1 (3rd lane). The commercial monoclonal UBQLN 2 antibody recognized both UBQLN1 and 2 band in b. (c) GFP-specific antibody detected the GFP-UBQLN1. (TIFF 864 kb)

References

  1. 1.
    Al-Sarraj S, King A, Troakes C, Smith B, Maekawa S, Bodi I, Rogelj B, Al-Chalabi A, Hortobagyi T, Shaw CE (2011) p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS. Acta Neuropathol 122:691–702PubMedCrossRefGoogle Scholar
  2. 2.
    Bertram L, Hiltunen M, Parkinson M, Ingelsson M, Lange C, Ramasamy K, Mullin K, Menon R, Sampson AJ, Hsiao MY, Elliott KJ, Velicelebi G, Moscarillo T, Hyman BT, Wagner SL, Becker KD, Blacker D, Tanzi RE (2005) Family-based association between Alzheimer’s disease and variants in UBQLN1. N Engl J Med 352:884–894PubMedCrossRefGoogle Scholar
  3. 3.
    Boxer AL, Mackenzie IR, Boeve BF, Baker M, Seeley WW, Crook R, Feldman H, Hsiung GY, Rutherford N, Laluz V, Whitwell J, Foti D, McDade E, Molano J, Karydas A, Wojtas A, Goldman J, Mirsky J, Sengdy P, Dearmond S, Miller BL, Rademakers R (2011) Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family. J Neurol Neurosurg Psychiatry 82:196–203PubMedCrossRefGoogle Scholar
  4. 4.
    Brooks BR, Miller RG, Swash M, Munsat TL (2000) El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 1:293–299PubMedCrossRefGoogle Scholar
  5. 5.
    Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B, Nakanishi A (1999) The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J Neurol Sci 169:13–21PubMedCrossRefGoogle Scholar
  6. 6.
    Conklin D, Holderman S, Whitmore TE, Maurer M, Feldhaus AL (2000) Molecular cloning, chromosome mapping and characterization of UBQLN3 a testis-specific gene that contains an ubiquitin-like domain. Gene 249:91–98PubMedCrossRefGoogle Scholar
  7. 7.
    Dejesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, Nicholson AM, Finch NA, Flynn H, Adamson J, Kouri N, Wojtas A, Sengdy P, Hsiung GY, Karydas A, Seeley WW, Josephs KA, Coppola G, Geschwind DH, Wszolek ZK, Feldman H, Knopman DS, Petersen RC, Miller BL, Dickson DW, Boylan KB, Graff-Radford NR, Rademakers R (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72:245–256PubMedCrossRefGoogle Scholar
  8. 8.
    Deng HX, Chen W, Hong ST, Boycott KM, Gorrie GH, Siddique N, Yang Y, Fecto F, Shi Y, Zhai H, Jiang H, Hirano M, Rampersaud E, Jansen GH, Donkervoort S, Bigio EH, Brooks BR, Ajroud K, Sufit RL, Haines JL, Mugnaini E, Pericak-Vance MA, Siddique T (2011) Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 477:211–215PubMedCrossRefGoogle Scholar
  9. 9.
    Deng HX, Hentati A, Tainer JA, Iqbal Z, Cayabyab A, Hung WY, Getzoff ED, Hu P, Herzfeldt B, Roos RP et al (1993) Amyotrophic lateral sclerosis and structural defects in Cu, Zn superoxide dismutase. Science 261:1047–1051PubMedCrossRefGoogle Scholar
  10. 10.
    Doi H, Mitsui K, Kurosawa M, Machida Y, Kuroiwa Y, Nukina N (2004) Identification of ubiquitin-interacting proteins in purified polyglutamine aggregates. FEBS Lett 571:171–176PubMedCrossRefGoogle Scholar
  11. 11.
    Elsasser S, Finley D (2005) Delivery of ubiquitinated substrates to protein-unfolding machines. Nat Cell Biol 7:742–749PubMedCrossRefGoogle Scholar
  12. 12.
    Folstein MF, Folstein SE, McHugh PR (1975) “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198PubMedCrossRefGoogle Scholar
  13. 13.
    Geser F, Lee VM, Trojanowski JQ (2010) Amyotrophic lateral sclerosis and frontotemporal lobar degeneration: a spectrum of TDP-43 proteinopathies. Neuropathology 30:103–112PubMedCrossRefGoogle Scholar
  14. 14.
    Geser F, Martinez-Lage M, Robinson J, Uryu K, Neumann M, Brandmeir NJ, Xie SX, Kwong LK, Elman L, McCluskey L, Clark CM, Malunda J, Miller BL, Zimmerman EA, Qian J, Van Deerlin V, Grossman M, Lee VM, Trojanowski JQ (2009) Clinical and pathological continuum of multisystem TDP-43 proteinopathies. Arch Neurol 66:180–189PubMedCrossRefGoogle Scholar
  15. 15.
    Geser F, Robinson JL, Malunda JA, Xie SX, Clark CM, Kwong LK, Moberg PJ, Moore EM, Van Deerlin VM, Lee VM, Arnold SE, Trojanowski JQ (2010) Pathological 43-kDa transactivation response DNA-binding protein in older adults with and without severe mental illness. Arch Neurol 67:1238–1250PubMedCrossRefGoogle Scholar
  16. 16.
    Gijselinck I, Van Langenhove T, van der Zee J, Sleegers K, Philtjens S, Kleinberger G, Janssens J, Bettens K, Van Cauwenberghe C, Pereson S, Engelborghs S, Sieben A, De Jonghe P, Vandenberghe R, Santens P, De Bleecker J, Maes G, Baumer V, Dillen L, Joris G, Cuijt I, Corsmit E, Elinck E, Van Dongen J, Vermeulen S, Van den Broeck M, Vaerenberg C, Mattheijssens M, Peeters K, Robberecht W, Cras P, Martin JJ, De Deyn PP, Cruts M, Van Broeckhoven C (2012) A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet Neurol 11:54–65PubMedCrossRefGoogle Scholar
  17. 17.
    Gorno-Tempini ML, Hillis AE, Weintraub S, Kertesz A, Mendez M, Cappa SF, Ogar JM, Rohrer JD, Black S, Boeve BF, Manes F, Dronkers NF, Vandenberghe R, Rascovsky K, Patterson K, Miller BL, Knopman DS, Hodges JR, Mesulam MM, Grossman M (2011) Classification of primary progressive aphasia and its variants. Neurology 76:1006–1014PubMedCrossRefGoogle Scholar
  18. 18.
    Hyman BT, Trojanowski JQ (1997) Consensus recommendations for the postmortem diagnosis of Alzheimer disease from the National Institute on Aging and the Reagan Institute Working Group on diagnostic criteria for the neuropathological assessment of Alzheimer disease. J Neuropathol Exp Neurol 56:1095–1097PubMedCrossRefGoogle Scholar
  19. 19.
    Kabashi E, Valdmanis PN, Dion P, Spiegelman D, McConkey BJ, Vande Velde C, Bouchard JP, Lacomblez L, Pochigaeva K, Salachas F, Pradat PF, Camu W, Meininger V, Dupre N, Rouleau GA (2008) TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 40:572–574PubMedCrossRefGoogle Scholar
  20. 20.
    Kertesz A, Davidson W, Fox H (1997) Frontal behavioral inventory: diagnostic criteria for frontal lobe dementia. Can J Neurol Sci 24:29–36PubMedGoogle Scholar
  21. 21.
    Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, Burrell JR, Zoing MC (2011) Amyotrophic lateral sclerosis. Lancet 377:942–955PubMedCrossRefGoogle Scholar
  22. 22.
    Kim SH, Shi Y, Hanson KA, Williams LM, Sakasai R, Bowler MJ, Tibbetts RS (2009) Potentiation of amyotrophic lateral sclerosis (ALS)-associated TDP-43 aggregation by the proteasome-targeting factor, ubiquilin 1. J Biol Chem 284:8083–8092PubMedCrossRefGoogle Scholar
  23. 23.
    King A, Maekawa S, Bodi I, Troakes C, Al-Sarraj S (2011) Ubiquitinated, p62 immunopositive cerebellar cortical neuronal inclusions are evident across the spectrum of TDP-43 proteinopathies but are only rarely additionally immunopositive for phosphorylation-dependent TDP-43. Neuropathology 31:239–249PubMedCrossRefGoogle Scholar
  24. 24.
    Kleijnen MF, Shih AH, Zhou P, Kumar S, Soccio RE, Kedersha NL, Gill G, Howley PM (2000) The hPLIC proteins may provide a link between the ubiquitination machinery and the proteasome. Mol Cell 6:409–419PubMedCrossRefGoogle Scholar
  25. 25.
    Kleyweg RP, van der Meche FG, Schmitz PI (1991) Interobserver agreement in the assessment of muscle strength and functional abilities in Guillain–Barre syndrome. Muscle Nerve 14:1103–1109PubMedCrossRefGoogle Scholar
  26. 26.
    Ko HS, Uehara T, Tsuruma K, Nomura Y (2004) Ubiquilin interacts with ubiquitylated proteins and proteasome through its ubiquitin-associated and ubiquitin-like domains. FEBS Lett 566:110–114PubMedCrossRefGoogle Scholar
  27. 27.
    Kovacs GG, Murrell JR, Horvath S, Haraszti L, Majtenyi K, Molnar MJ, Budka H, Ghetti B, Spina S (2009) TARDBP variation associated with frontotemporal dementia, supranuclear gaze palsy, and chorea. Mov Disord 24:1843–1847PubMedCrossRefGoogle Scholar
  28. 28.
    Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, Davis A, Gilchrist J, Kasarskis EJ, Munsat T, Valdmanis P, Rouleau GA, Hosler BA, Cortelli P, de Jong PJ, Yoshinaga Y, Haines JL, Pericak-Vance MA, Yan J, Ticozzi N, Siddique T, McKenna-Yasek D, Sapp PC, Horvitz HR, Landers JE, Brown RH Jr (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323:1205–1208PubMedCrossRefGoogle Scholar
  29. 29.
    Lezak M (1983) Neuropsychological assessment. Oxford University Press, New YorkGoogle Scholar
  30. 30.
    Libon DJ, Massimo L, Moore P, Coslett HB, Chatterjee A, Aguirre GK, Rice A, Vesely L, Grossman M (2007) Screening for frontotemporal dementias and Alzheimer’s disease with the Philadelphia Brief Assessment of Cognition: a preliminary analysis. Dement Geriatr Cogn Disord 24:441–447PubMedCrossRefGoogle Scholar
  31. 31.
    Lim PJ, Danner R, Liang J, Doong H, Harman C, Srinivasan D, Rothenberg C, Wang H, Ye Y, Fang S, Monteiro MJ (2009) Ubiquilin and p97/VCP bind erasin, forming a complex involved in ERAD. J Cell Biol 187:201–217PubMedCrossRefGoogle Scholar
  32. 32.
    Mackenzie IR, Neumann M, Baborie A, Sampathu DM, Du Plessis D, Jaros E, Perry RH, Trojanowski JQ, Mann DM, Lee VM (2011) A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol 122:111–113PubMedCrossRefGoogle Scholar
  33. 33.
    Mackenzie IR, Neumann M, Bigio EH, Cairns NJ, Alafuzoff I, Kril J, Kovacs GG, Ghetti B, Halliday G, Holm IE, Ince PG, Kamphorst W, Revesz T, Rozemuller AJ, Kumar-Singh S, Akiyama H, Baborie A, Spina S, Dickson DW, Trojanowski JQ, Mann DM (2010) Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol 119:1–4PubMedCrossRefGoogle Scholar
  34. 34.
    Mah AL, Perry G, Smith MA, Monteiro MJ (2000) Identification of ubiquilin, a novel presenilin interactor that increases presenilin protein accumulation. J Cell Biol 151:847–862PubMedCrossRefGoogle Scholar
  35. 35.
    Massey LK, Mah AL, Monteiro MJ (2005) Ubiquilin regulates presenilin endoproteolysis and modulates gamma-secretase components, Pen-2 and nicastrin. Biochem J 391:513–525PubMedCrossRefGoogle Scholar
  36. 36.
    Murray ME, Dejesus-Hernandez M, Rutherford NJ, Baker M, Duara R, Graff-Radford NR, Wszolek ZK, Ferman TJ, Josephs KA, Boylan KB, Rademakers R, Dickson DW (2011) Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72. Acta Neuropathol 122:673–690PubMedCrossRefGoogle Scholar
  37. 37.
    N’Diaye EN, Kajihara KK, Hsieh I, Morisaki H, Debnath J, Brown EJ (2009) PLIC proteins or ubiquilins regulate autophagy-dependent cell survival during nutrient starvation. EMBO Rep 10:173–179PubMedCrossRefGoogle Scholar
  38. 38.
    Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF (1998) Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 51:1546–1554PubMedCrossRefGoogle Scholar
  39. 39.
    Neumann M, Kwong LK, Lee EB, Kremmer E, Flatley A, Xu Y, Forman MS, Troost D, Kretzschmar HA, Trojanowski JQ, Lee VM (2009) Phosphorylation of S409/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathies. Acta Neuropathol 117:137–149PubMedCrossRefGoogle Scholar
  40. 40.
    Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133PubMedCrossRefGoogle Scholar
  41. 41.
    Rascovsky K, Hodges JR, Knopman D, Mendez MF, Kramer JH, Neuhaus J, van Swieten JC, Seelaar H, Dopper EG, Onyike CU, Hillis AE, Josephs KA, Boeve BF, Kertesz A, Seeley WW, Rankin KP, Johnson JK, Gorno-Tempini ML, Rosen H, Prioleau-Latham CE, Lee A, Kipps CM, Lillo P, Piguet O, Rohrer JD, Rossor MN, Warren JD, Fox NC, Galasko D, Salmon DP, Black SE, Mesulam M, Weintraub S, Dickerson BC, Diehl-Schmid J, Pasquier F, Deramecourt V, Lebert F, Pijnenburg Y, Chow TW, Manes F, Grafman J, Cappa SF, Freedman M, Grossman M, Miller BL (2011) Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 134:2456–2477PubMedCrossRefGoogle Scholar
  42. 42.
    Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR, Schymick JC, Laaksovirta H, van Swieten JC, Myllykangas L, Kalimo H, Paetau A, Abramzon Y, Remes AM, Kaganovich A, Scholz SW, Duckworth J, Ding J, Harmer DW, Hernandez DG, Johnson JO, Mok K, Ryten M, Trabzuni D, Guerreiro RJ, Orrell RW, Neal J, Murray A, Pearson J, Jansen IE, Sondervan D, Seelaar H, Blake D, Young K, Halliwell N, Callister JB, Toulson G, Richardson A, Gerhard A, Snowden J, Mann D, Neary D, Nalls MA, Peuralinna T, Jansson L, Isoviita VM, Kaivorinne AL, Holtta-Vuori M, Ikonen E, Sulkava R, Benatar M, Wuu J, Chio A, Restagno G, Borghero G, Sabatelli M, Heckerman D, Rogaeva E, Zinman L, Rothstein JD, Sendtner M, Drepper C, Eichler EE, Alkan C, Abdullaev Z, Pack SD, Dutra A, Pak E, Hardy J, Singleton A, Williams NM, Heutink P, Pickering-Brown S, Morris HR, Tienari PJ, Traynor BJ (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72:257–268PubMedCrossRefGoogle Scholar
  43. 43.
    Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O’Regan JP, Deng HX et al (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362:59–62PubMedCrossRefGoogle Scholar
  44. 44.
    Rosso SM, Donker Kaat L, Baks T, Joosse M, de Koning I, Pijnenburg Y, de Jong D, Dooijes D, Kamphorst W, Ravid R, Niermeijer MF, Verheij F, Kremer HP, Scheltens P, van Duijn CM, Heutink P, van Swieten JC (2003) Frontotemporal dementia in The Netherlands: patient characteristics and prevalence estimates from a population-based study. Brain 126:2016–2022PubMedCrossRefGoogle Scholar
  45. 45.
    Rothenberg C, Monteiro MJ (2010) Ubiquilin at a crossroads in protein degradation pathways. Autophagy 6:979–980PubMedCrossRefGoogle Scholar
  46. 46.
    Rothenberg C, Srinivasan D, Mah L, Kaushik S, Peterhoff CM, Ugolino J, Fang S, Cuervo AM, Nixon RA, Monteiro MJ (2010) Ubiquilin functions in autophagy and is degraded by chaperone-mediated autophagy. Hum Mol Genet 19:3219–3232PubMedCrossRefGoogle Scholar
  47. 47.
    Rutherford NJ, Zhang YJ, Baker M, Gass JM, Finch NA, Xu YF, Stewart H, Kelley BJ, Kuntz K, Crook RJ, Sreedharan J, Vance C, Sorenson E, Lippa C, Bigio EH, Geschwind DH, Knopman DS, Mitsumoto H, Petersen RC, Cashman NR, Hutton M, Shaw CE, Boylan KB, Boeve B, Graff-Radford NR, Wszolek ZK, Caselli RJ, Dickson DW, Mackenzie IR, Petrucelli L, Rademakers R (2008) Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis. PLoS Genet 4:e1000193PubMedCrossRefGoogle Scholar
  48. 48.
    Schnell SA, Staines WA, Wessendorf MW (1999) Reduction of lipofuscin-like autofluorescence in fluorescently labeled tissue. J Histochem Cytochem 47:719–730PubMedCrossRefGoogle Scholar
  49. 49.
    Simon-Sanchez J, Dopper EG, Cohn-Hokke PE, Hukema RK, Nicolaou N, Seelaar H, de Graaf JR, de Koning I, van Schoor NM, Deeg DJ, Smits M, Raaphorst J, van den Berg LH, Schelhaas HJ, De Die-Smulders CE, Majoor-Krakauer D, Rozemuller AJ, Willemsen R, Pijnenburg YA, Heutink P, van Swieten JC (2012) The clinical and pathological phenotype of C9orf72 hexanucleotide repeat expansions. Brain [Epub ahead of print]Google Scholar
  50. 50.
    Snowden JS, Rollinson S, Thompson JC, Harris JM, Stopford CL, Richardson AM, Jones M, Gerhard A, Davidson YS, Robinson A, Gibbons L, Hu Q, Duplessis D, Neary D, Mann DM, Pickering-Brown SM (2012) Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain [Epub ahead of print]Google Scholar
  51. 51.
    Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, Ackerley S, Durnall JC, Williams KL, Buratti E, Baralle F, de Belleroche J, Mitchell JD, Leigh PN, Al-Chalabi A, Miller CC, Nicholson G, Shaw CE (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319:1668–1672PubMedCrossRefGoogle Scholar
  52. 52.
    Stewart H, Rutherford NJ, Briemberg H, Krieger C, Cashman N, Fabros M, Baker M, Fok A, Dejesus-Hernandez M, Eisen A, Rademakers R, Mackenzie IR (2012) Clinical and pathological features of amyotrophic lateral sclerosis caused by mutation in the C9ORF72 gene on chromosome 9p. Acta Neuropathol 123:409–417PubMedCrossRefGoogle Scholar
  53. 53.
    Stieren ES, El Ayadi A, Xiao Y, Siller E, Landsverk ML, Oberhauser AF, Barral JM, Boehning D (2011) Ubiquilin-1 is a molecular chaperone for the amyloid precursor protein. J Biol Chem 286:35689–35698PubMedCrossRefGoogle Scholar
  54. 54.
    Troakes C, Maekawa S, Wijesekera L, Rogelj B, Siklos L, Bell C, Smith B, Newhouse S, Vance C, Johnson L, Hortobagyi T, Shatunov A, Al-Chalabi A, Leigh N, Shaw CE, King A, Al-Sarraj S (2011) An MND/ALS phenotype associated with C9orf72 repeat expansion: abundant p62-positive, TDP-43-negative inclusions in cerebral cortex, hippocampus and cerebellum but without associated cognitive decline. Neuropathology [Epub ahead of print]Google Scholar
  55. 55.
    Uryu K, Nakashima-Yasuda H, Forman MS, Kwong LK, Clark CM, Grossman M, Miller BL, Kretzschmar HA, Lee VM, Trojanowski JQ, Neumann M (2008) Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies. J Neuropathol Exp Neurol 67:555–564PubMedCrossRefGoogle Scholar
  56. 56.
    Van Langenhove T, van der Zee J, Sleegers K, Engelborghs S, Vandenberghe R, Gijselinck I, Van den Broeck M, Mattheijssens M, Peeters K, De Deyn PP, Cruts M, Van Broeckhoven C (2010) Genetic contribution of FUS to frontotemporal lobar degeneration. Neurology 74:366–371PubMedCrossRefGoogle Scholar
  57. 57.
    Vance C, Rogelj B, Hortobagyi T, De Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B, Ruddy D, Wright P, Ganesalingam J, Williams KL, Tripathi V, Al-Saraj S, Al-Chalabi A, Leigh PN, Blair IP, Nicholson G, de Belleroche J, Gallo JM, Miller CC, Shaw CE (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323:1208–1211PubMedCrossRefGoogle Scholar
  58. 58.
    Viswanathan J, Haapasalo A, Bottcher C, Miettinen R, Kurkinen KM, Lu A, Thomas A, Maynard CJ, Romano D, Hyman BT, Berezovska O, Bertram L, Soininen H, Dantuma NP, Tanzi RE, Hiltunen M (2011) Alzheimer’s disease-associated ubiquilin-1 regulates presenilin-1 accumulation and aggresome formation. Traffic 12:330–348PubMedCrossRefGoogle Scholar
  59. 59.
    Wang H, Lim PJ, Yin C, Rieckher M, Vogel BE, Monteiro MJ (2006) Suppression of polyglutamine-induced toxicity in cell and animal models of Huntington’s disease by ubiquilin. Hum Mol Genet 15:1025–1041PubMedCrossRefGoogle Scholar
  60. 60.
    Wang H, Monteiro MJ (2007) Ubiquilin interacts and enhances the degradation of expanded-polyglutamine proteins. Biochem Biophys Res Commun 360:423–427PubMedCrossRefGoogle Scholar
  61. 61.
    Wang H, Monteiro MJ (2007) Ubiquilin overexpression reduces GFP-polyalanine-induced protein aggregates and toxicity. Exp Cell Res 313:2810–2820PubMedCrossRefGoogle Scholar
  62. 62.
    Wooten MW, Hu X, Babu JR, Seibenhener ML, Geetha T, Paine MG, Wooten MC (2006) Signaling, polyubiquitination, trafficking, and inclusions: sequestosome 1/p62’s role in neurodegenerative disease. J Biomed Biotechnol 2006:62079PubMedCrossRefGoogle Scholar
  63. 63.
    Wu AL, Wang J, Zheleznyak A, Brown EJ (1999) Ubiquitin-related proteins regulate interaction of vimentin intermediate filaments with the plasma membrane. Mol Cell 4:619–625PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Johannes Brettschneider
    • 1
    • 5
  • Vivianna M. Van Deerlin
    • 1
    • 2
  • John L. Robinson
    • 1
  • Linda Kwong
    • 1
  • Edward B. Lee
    • 2
  • Yousuf O. Ali
    • 1
  • Nathaniel Safren
    • 3
  • Mervyn J. Monteiro
    • 3
  • Jon B. Toledo
    • 1
  • Lauren Elman
    • 4
  • Leo McCluskey
    • 4
  • David J. Irwin
    • 1
    • 4
  • Murray Grossman
    • 4
  • Laura Molina-Porcel
    • 1
  • Virginia M.-Y. Lee
    • 1
    • 2
  • John Q. Trojanowski
    • 1
    • 2
  1. 1.Center for Neurodegenerative Disease Research (CNDR)University of Pennsylvania School of MedicinePhiladelphiaUSA
  2. 2.Department of Pathology and Laboratory MedicineUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  3. 3.Center for Biomedical Engineering and Technology and Department of Anatomy and NeurobiologyUniversity of MarylandBaltimoreUSA
  4. 4.Department of NeurologyUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  5. 5.Department of NeurologyUniversity of UlmUlmGermany

Personalised recommendations