Skip to main content

Advertisement

Springer Nature Link
Log in

Mutations in SQSTM1 encoding p62 in amyotrophic lateral sclerosis: genetics and neuropathology

  • Original Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Mutations in SQSTM1 encoding the sequestosome 1/p62 protein have recently been identified in familial and sporadic cases of amyotrophic lateral sclerosis (ALS). p62 is a component of the ubiquitin inclusions detected in degenerating neurons in ALS patients. We sequenced SQSTM1 in 90 French patients with familial ALS (FALS) and 74 autopsied ALS cases with sporadic ALS (SALS). We identified, at the heterozygote state, one missense c.1175C>T, p.Pro392Leu (exon 8) in one of our FALS and one substitution in intron 7 (the c.1165+1G>A, previously called IVS7+1 G-A, A390X) affecting the exon 7 splicing site in one SALS. These mutations that are located in the ubiquitin-associated domain (UBA domain) of the p62 protein have already been described in Paget’s disease and ALS patients carrying these mutations had both concomitant Paget’s disease. However, we also identified two novel missense mutations in two SALS: the c.259A>G, p.Met87Val in exon 2 and the c.304A>G, p.Lys102Glu in exon 3. These mutations that were not detected in 360 control subjects are possibly pathogenic. Neuropathology analysis of three patients carrying SQSTM1 variants revealed the presence of large round p62 inclusions in motor neurons, and immunoblot analysis showed an increased p62 and TDP-43 protein levels in the spinal cord. Our results confirm that SQSTM1 gene mutations could be the cause or genetic susceptibility factor of ALS in some patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  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 122:691–702

    Article  PubMed  CAS  Google Scholar 

  2. Albagha OM, Visconti MR, Alonso N, Langston AL, Cundy T, Dargie R, Dunlop MG, Fraser WD, Hooper MJ, Isaia G, Nicholson GC, del Pino Montes J, Gonzalez-Sarmiento R, di Stefano M, Tenesa A, Walsh JP, Ralston SH (2010) Genome-wide association study identifies variants at CSF1, OPTN and TNFRSF11A as genetic risk factors for Paget’s disease of bone. Nat Genet 42:520–524

    Google Scholar 

  3. Brady OA, Meng P, Zheng Y, Mao Y, Hu F (2011) Regulation of TDP-43 aggregation by phosphorylation and p62/SQSTM1. J Neurochem 116:248–259

    Article  PubMed  CAS  Google Scholar 

  4. Brettschneider J, Libon DJ, Toledo JB, Xie SX, McCluskey L, Elman L, Geser F, Lee VM, Grossman M, Trojanowski JQ (2012) Microglial activation and TDP-43 pathology correlate with executive dysfunction in amyotrophic lateral sclerosis. Acta Neuropathol 123:395–407

    Article  PubMed  CAS  Google Scholar 

  5. Brettschneider J, Van Deerlin VM, Robinson JL, Kwong L, Lee EB, Ali YO, Safren N, Monteiro MJ, Toledo JB, Elman L, McCluskey L, Irwin DJ, Grossman M, Molina-Porcel L, Lee VM, Trojanowski JQ (2012) Pattern of ubiquilin pathology in ALS and FTLD indicates presence of C9ORF72 hexanucleotide expansion. Acta Neuropathol 123:825–839

    Article  PubMed  Google Scholar 

  6. 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 1:293–299

    Article  PubMed  CAS  Google Scholar 

  7. Cavey JR, Ralston SH, Sheppard PW, Ciani B, Gallagher TR, Long JE, Searle MS, Layfield R (2006) Loss of ubiquitin binding is a unifying mechanism by which mutations of SQSTM1 cause Paget’s disease of bone. Calcif Tissue Int 78:271–277

    Article  PubMed  CAS  Google Scholar 

  8. Collet C, Michou L, Audran M, Chasseigneaux S, Hilliquin P, Bardin T, Lemaire I, Cornelis F, Launay JM, Orcel P, Laplanche JL (2007) Paget’s disease of bone in the French population: novel SQSTM1 mutations, functional analysis, and genotype-phenotype correlations. J Bone Miner Res 22:310–317

    Article  PubMed  CAS  Google Scholar 

  9. Cooper C, Schafheutle K, Dennison E, Kellingray S, Guyer P, Barker D (1999) The epidemiology of Paget’s disease in Britain: is the prevalence decreasing? J Bone Miner Res 14:192–197

    Article  PubMed  CAS  Google Scholar 

  10. Dai RM, Li CC (2001) Valosin-containing protein is a multi-ubiquitin chain-targeting factor required in ubiquitin-proteasome degradation. Nat Cell Biol 3:740–744

    Article  PubMed  CAS  Google Scholar 

  11. Daroszewska A, van ‘t Hof RJ, Rojas JA, Layfield R, Landao-Basonga E, Rose L, Rose K, Ralston SH (2011) A point mutation in the ubiquitin-associated domain of SQSMT1 is sufficient to cause a Paget’s disease-like disorder in mice. Hum Mol Genet 20:2734–2744

    Google Scholar 

  12. 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 72:245–256

    Article  PubMed  CAS  Google Scholar 

  13. Falchetti A, Di Stefano M, Marini F, Ortolani S, Ulivieri MF, Bergui S, Masi L, Cepollaro C, Benucci M, Di Munno O, Rossini M, Adami S, Del Puente A, Isaia G, Torricelli F, Brandi ML (2009) Genetic epidemiology of Paget’s disease of bone in Italy: sequestosome1/p62 gene mutational test and haplotype analysis at 5q35 in a large representative series of sporadic and familial Italian cases of Paget’s disease of bone. Calcif Tissue Int 84:20–37

    Article  PubMed  CAS  Google Scholar 

  14. Fecto F, Yan J, Vemula SP, Liu E, Yang Y, Chen W, Zheng JG, Shi Y, Siddique N, Arrat H, Donkervoort S, Ajroud-Driss S, Sufit RL, Heller SL, Deng HX, Siddique T (2011) SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis. Arch Neurol 68:1440–1446

    Article  PubMed  Google Scholar 

  15. Geetha T, Vishwaprakash N, Sycheva M, Babu JR (2012) Sequestosome 1/p62: across diseases. Biomarkers 17:99–103

    Article  PubMed  CAS  Google Scholar 

  16. 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 67:1238–1250

    Article  PubMed  Google Scholar 

  17. Geser F, Stein B, Partain M, Elman LB, McCluskey LF, Xie SX, Van Deerlin VM, Kwong LK, Lee VM, Trojanowski JQ (2011) Motor neuron disease clinically limited to the lower motor neuron is a diffuse TDP-43 proteinopathy. Acta Neuropathol 121:509–517

    Article  PubMed  Google Scholar 

  18. Gleason CE, Ordureau A, Gourlay R, Arthur JS, Cohen P (2011) Polyubiquitin binding to optineurin is required for optimal activation of TANK-binding kinase 1 and production of interferon beta. J Biol Chem 286:35663–35674

    Article  PubMed  CAS  Google Scholar 

  19. Goode A, Layfield R (2010) Recent advances in understanding the molecular basis of Paget disease of bone. J Clin Pathol 63:199–203

    Article  PubMed  CAS  Google Scholar 

  20. Hamdy RC (1995) Clinical features and pharmacologic treatment of Paget’s disease. Endocrinol Metab Clin North Am 24:421–436

    PubMed  CAS  Google Scholar 

  21. Hart MP, Brettschneider J, Lee VM, Trojanowski JQ, Gitler AD (2012) Distinct TDP-43 pathology in ALS patients with ataxin 2 intermediate-length polyQ expansions. Acta Neuropathol 124:221–230

    Article  PubMed  CAS  Google Scholar 

  22. Hernandez Lain A, Millecamps S, Dubourg O, Salachas F, Bruneteau G, Lacomblez L, LeGuern E, Seilhean D, Duyckaerts C, Meininger V, Mallet J, Pradat PF (2011) Abnormal TDP-43 and FUS proteins in muscles of sporadic IBM: similarities in a TARDBP-linked ALS patient. J Neurol Neurosurg Psychiatry 82:1414–1416

    Article  PubMed  Google Scholar 

  23. Hirano M, Nakamura Y, Saigoh K, Sakamoto H, Ueno S, Isono C, Miyamoto K, Akamatsu M, Mitsui Y, Kusunoki S (2013) Mutations in the gene encoding p62 in Japanese patients with amyotrophic lateral sclerosis. Neurology 80:458–463

    Article  PubMed  CAS  Google Scholar 

  24. Hocking LJ, Lucas GJ, Daroszewska A, Mangion J, Olavesen M, Cundy T, Nicholson GC, Ward L, Bennett ST, Wuyts W, Van Hul W, Ralston SH (2002) Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and sporadic Paget’s disease. Hum Mol Genet 11:2735–2739

    Article  PubMed  CAS  Google Scholar 

  25. Johnson JO, Mandrioli J, Benatar M, Abramzon Y, Van Deerlin VM, Trojanowski JQ, Gibbs JR, Brunetti M, Gronka S, Wuu J, Ding J, McCluskey L, Martinez-Lage M, Falcone D, Hernandez DG, Arepalli S, Chong S, Schymick JC, Rothstein J, Landi F, Wang YD, Calvo A, Mora G, Sabatelli M, Monsurro MR, Battistini S, Salvi F, Spataro R, Sola P, Borghero G, Galassi G, Scholz SW, Taylor JP, Restagno G, Chio A, Traynor BJ (2010) Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 68:857–864

    Article  PubMed  CAS  Google Scholar 

  26. Kuusisto E, Salminen A, Alafuzoff I (2001) Ubiquitin-binding protein p62 is present in neuronal and glial inclusions in human tauopathies and synucleinopathies. NeuroReport 12:2085–2090

    Article  PubMed  CAS  Google Scholar 

  27. Laurin N, Brown JP, Morissette J, Raymond V (2002) Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone. Am J Hum Genet 70:1582–1588

    Article  PubMed  CAS  Google Scholar 

  28. Mackenzie IR, Bigio EH, Ince PG, Geser F, Neumann M, Cairns NJ, Kwong LK, Forman MS, Ravits J, Stewart H, Eisen A, McClusky L, Kretzschmar HA, Monoranu CM, Highley JR, Kirby J, Siddique T, Shaw PJ, Lee VM, Trojanowski JQ (2007) Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol 61:427–434

    Article  PubMed  CAS  Google Scholar 

  29. 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 122:111–113

    Article  PubMed  Google Scholar 

  30. Maruyama H, Morino H, Ito H, Izumi Y, Kato H, Watanabe Y, Kinoshita Y, Kamada M, Nodera H, Suzuki H, Komure O, Matsuura S, Kobatake K, Morimoto N, Abe K, Suzuki N, Aoki M, Kawata A, Hirai T, Kato T, Ogasawara K, Hirano A, Takumi T, Kusaka H, Hagiwara K, Kaji R, Kawakami H (2010) Mutations of optineurin in amyotrophic lateral sclerosis. Nature 465:223–226

    Article  PubMed  CAS  Google Scholar 

  31. Michou L, Collet C, Laplanche JL, Orcel P, Cornelis F (2006) Genetics of Paget’s disease of bone. Joint Bone Spine 73:243–248

    Article  PubMed  CAS  Google Scholar 

  32. Michou L, Collet C, Morissette J, Audran M, Thomas T, Gagnon E, Launay JM, Laplanche JL, Brown JP, Orcel P (2012) Epidemiogenetic study of French families with Paget’s disease of bone. Joint Bone Spine 79:393–398

    Article  PubMed  Google Scholar 

  33. Millecamps S, Boillee S, Chabrol E, Camu W, Cazeneuve C, Salachas F, Pradat PF, Danel-Brunaud V, Vandenberghe N, Corcia P, Le Forestier N, Lacomblez L, Bruneteau G, Seilhean D, Brice A, Feingold J, Meininger V, LeGuern E (2011) Screening of OPTN in French familial amyotrophic lateral sclerosis. Neurobiol Aging 32:557 e511–e553

    Google Scholar 

  34. Millecamps S, Boillee S, Le Ber I, Seilhean D, Teyssou E, Giraudeau M, Moigneu C, Vandenberghe N, Danel-Brunaud V, Corcia P, Pradat PF, Le Forestier N, Lacomblez L, Bruneteau G, Camu W, Brice A, Cazeneuve C, Leguern E, Meininger V, Salachas F (2012) Phenotype difference between ALS patients with expanded repeats in C9ORF72 and patients with mutations in other ALS-related genes. J Med Genet 49:258–263

    Article  PubMed  CAS  Google Scholar 

  35. Millecamps S, Corcia P, Cazeneuve C, Boillee S, Seilhean D, Danel-Brunaud V, Vandenberghe N, Pradat PF, Le Forestier N, Lacomblez L, Bruneteau G, Camu W, Brice A, Meininger V, LeGuern E, Salachas F (2012) Mutations in UBQLN2 are rare in French amyotrophic lateral sclerosis. Neurobiol Aging 33:839 e831–e833

    Google Scholar 

  36. Millecamps S, Da Barroca S, Cazeneuve C, Salachas F, Pradat PF, Danel-Brunaud V, Vandenberghe N, Lacomblez L, Le Forestier N, Bruneteau G, Camu W, Brice A, Meininger V, LeGuern E (2010) Questioning on the role of D amino acid oxidase in familial amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 107:E107 (author reply E108)

  37. Millecamps S, Salachas F, Cazeneuve C, Gordon P, Bricka B, Camuzat A, Guillot-Noel L, Russaouen O, Bruneteau G, Pradat PF, Le Forestier N, Vandenberghe N, Danel-Brunaud V, Guy N, Thauvin-Robinet C, Lacomblez L, Couratier P, Hannequin D, Seilhean D, Le Ber I, Corcia P, Camu W, Brice A, Rouleau G, Leguern E, Meininger V (2010) SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral sclerosis: genotype–phenotype correlations. J Med Genet 47:554–560

    Article  PubMed  CAS  Google Scholar 

  38. Mizuno Y, Amari M, Takatama M, Aizawa H, Mihara B, Okamoto K (2006) Immunoreactivities of p62, an ubiqutin-binding protein, in the spinal anterior horn cells of patients with amyotrophic lateral sclerosis. J Neurol Sci 249:13–18

    Article  PubMed  CAS  Google Scholar 

  39. 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 314:130–133

    Article  PubMed  CAS  Google Scholar 

  40. Okamoto K, Hirai S, Amari M, Watanabe M, Sakurai A (1993) Bunina bodies in amyotrophic lateral sclerosis immunostained with rabbit anti-cystatin C serum. Neurosci Lett 162:125–128

    Article  PubMed  CAS  Google Scholar 

  41. Pikkarainen M, Hartikainen P, Alafuzoff I (2008) Neuropathologic features of frontotemporal lobar degeneration with ubiquitin-positive inclusions visualized with ubiquitin-binding protein p62 immunohistochemistry. J Neuropathol Exp Neurol 67:280–298

    Article  PubMed  Google Scholar 

  42. Ramesh Babu J, Lamar Seibenhener M, Peng J, Strom AL, Kemppainen R, Cox N, Zhu H, Wooten MC, Diaz-Meco MT, Moscat J, Wooten MW (2008) Genetic inactivation of p62 leads to accumulation of hyperphosphorylated tau and neurodegeneration. J Neurochem 106:107–120

    Article  PubMed  CAS  Google Scholar 

  43. 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 72:257–268

    Article  PubMed  CAS  Google Scholar 

  44. Rubino E, Rainero I, Chio A, Rogaeva E, Galimberti D, Fenoglio P, Grinberg Y, Isaia G, Calvo A, Gentile S, Bruni AC, St George-Hyslop PH, Scarpini E, Gallone S, Pinessi L (2012) SQSTM1 mutations in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Neurology 79:1556–1562

  45. Tanji K, Zhang HX, Mori F, Kakita A, Takahashi H, Wakabayashi K (2012) p62/sequestosome 1 binds to TDP-43 in brains with frontotemporal lobar degeneration with TDP-43 inclusions. J Neurosci Res 90:2034–2042

    Article  PubMed  CAS  Google Scholar 

  46. Vadlamudi RK, Joung I, Strominger JL, Shin J (1996) p62, a phosphotyrosine-independent ligand of the SH2 domain of p56lck, belongs to a new class of ubiquitin-binding proteins. J Biol Chem 271:20235–20237

    Article  PubMed  CAS  Google Scholar 

  47. Watts GD, Wymer J, Kovach MJ, Mehta SG, Mumm S, Darvish D, Pestronk A, Whyte MP, Kimonis VE (2004) Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet 36:377–381

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We are grateful to the patients and their families. We thank the Généthon cell and DNA bank (Evry, France) and the CRicm DNA and cell bank (Paris, France) for patients’ DNA and the genotyping and sequencing platform facilities of the ICM (Paris, France). This work was financed by the Association pour la Recherche sur la Sclérose latérale amyotrophique et autres maladies du motoneurone (ARSla, France), the Association française contre les myopathies (AFM, France) and the Fondation NRJ-Institut de France (France). Protocols were approved by the Medical Research Ethics Committee of “Assistance Publique Hôpitaux de Paris” and all participants signed a consent form for the research.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. INSERM UMR_S975, CNRS UMR7225, Université Pierre et Marie Curie-Sorbonne Universités, Hôpital Pitié-Salpêtrière, Paris, France

    Elisa Teyssou, Séverine Boillée, Eric LeGuern, François Salachas, Danielle Seilhean & Stéphanie Millecamps

  2. Département de Neuropathologie, Assistance Publique Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière, Paris, France

    Takahiro Takeda, Vincent Lebon, Brahima Doukouré, Guillaume Bataillon, Véronique Sazdovitch & Danielle Seilhean

  3. Département de Génétique et Cytogénétique, APHP, Unité Fonctionnelle de neurogénétique moléculaire et cellulaire, Hôpital Pitié-Salpêtrière, Paris, France

    Cécile Cazeneuve & Eric LeGuern

  4. Fédération des Maladies du Système Nerveux, APHP, Centre de référence maladies rares SLA, Hôpital Pitié-Salpêtrière, Paris, France

    Vincent Meininger & François Salachas

  5. Centre de Recherche de l’Institut du Cerveau et de la Moelle épinière, Groupe hospitalier Pitié-Salpêtrière, 83, Bd de l’Hôpital, 75013, Paris, France

    Stéphanie Millecamps

Authors
  1. Elisa Teyssou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takahiro Takeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vincent Lebon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Séverine Boillée
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Brahima Doukouré
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Guillaume Bataillon
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Véronique Sazdovitch
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Cécile Cazeneuve
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Vincent Meininger
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Eric LeGuern
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. François Salachas
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Danielle Seilhean
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Stéphanie Millecamps
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stéphanie Millecamps.

Additional information

D. Seilhean and S. Millecamps contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (JPG 536 kb)

Supplementary material 2 (DOC 165 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Teyssou, E., Takeda, T., Lebon, V. et al. Mutations in SQSTM1 encoding p62 in amyotrophic lateral sclerosis: genetics and neuropathology. Acta Neuropathol 125, 511–522 (2013). https://doi.org/10.1007/s00401-013-1090-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-013-1090-0

Keywords

Search

Navigation