Skip to main content

Advertisement

SpringerLink
Log in

How does the genetic assassin select its neuronal target?

  • Published:
Mammalian Genome Aims and scope Submit manuscript

Abstract

Through many different routes of analysis, including human familial studies and animal models, we are identifying an increasing number of genes that are causative for human neurodegenerative disease and are now in a position for many such disorders to dissect the molecular pathology that gives rise to neuronal death. Yet a paradox remains: The majority of the genes identified cause neurodegeneration in specific neuronal subtypes, but the genes themselves are ubiquitously expressed. Furthermore, the different mutations in the same gene may cause quite different types of neurodegeneration. Something in our understanding of neurodegenerative disease is clearly missing, and we refer to this as the phenomenon of “neuronal targeting.” Here we discuss possible explanations for neuronal targeting, why specific neuronal subtypes are vulnerable to specific mutations in ubiquitously expressed genes.

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 excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Benajiba L, Le Ber I, Camuzat A, Lacoste M, Thomas-Anterion C et al (2009) TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration. Ann Neurol 65:470–474

    Article  PubMed  CAS  Google Scholar 

  • Bertram L, Tanzi RE (2005) The genetic epidemiology of neurodegenerative disease. J Clin Invest 115:1449–1457

    Article  PubMed  CAS  Google Scholar 

  • Boillee S, Vande Velde C, Cleveland DW (2006) ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron 52:39–59

    Article  PubMed  CAS  Google Scholar 

  • Borchelt DR, Koliatsos VE, Guarnieri M, Pardo CA, Sisodia SS et al (1994) Rapid anterograde axonal transport of the cellular prion glycoprotein in the peripheral and central nervous systems. J Biol Chem 269:14711–14714

    PubMed  CAS  Google Scholar 

  • Bredesen DE, Ellerby LM, Hart PJ, WiedauPazos M, Valentine JS (1997) Do posttranslational modifications of CuZnSOD lead to sporadic amyotrophic lateral sclerosis? Ann Neurol 42:135–137

    Article  PubMed  CAS  Google Scholar 

  • Brickell KL, Leverenz JB, Steinbart EJ, Rumbaugh M, Schellenberg GD et al (2007) Clinicopathological concordance and discordance in three monozygotic twin pairs with familial Alzheimer’s disease. J Neurol Neurosurg Psychiatry 78:1050–1055

    Article  PubMed  Google Scholar 

  • Brown P, Preece M, Brandel JP, Sato T, McShane L et al (2000) Iatrogenic Creutzfeldt-Jakob disease at the millennium. Neurology 55:1075–1081

    PubMed  CAS  Google Scholar 

  • Chen-Plotkin AS, Yuan W, Anderson C, Wood EM, Hurtig HI et al (2008) Corticobasal syndrome and primary progressive aphasia as manifestations of LRRK2 gene mutations. Neurology 70:521–527

    Article  PubMed  CAS  Google Scholar 

  • Chia R, Tattum MH, Jones S, Collinge J, Fisher EM et al (2010) Superoxide dismutase 1 and tgSOD1 mouse spinal cord seed fibrils, suggesting a propagative cell death mechanism in amyotrophic lateral sclerosis. PLoS ONE 5:e10627

    Article  PubMed  Google Scholar 

  • Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S et al (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 11:909–913

    Article  PubMed  CAS  Google Scholar 

  • Clement AM, Nguyen MD, Roberts EA, Garcia ML, Boillee S et al (2003) Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 302:113–117

    Article  PubMed  CAS  Google Scholar 

  • Collinge J (1999) Variant Creutzfeldt-Jakob disease. Lancet 354:317–323

    Article  PubMed  CAS  Google Scholar 

  • Collinge J (2001) Prion diseases of humans and animals: their causes and molecular basis. Annu Rev Neurosci 24:519–550

    Article  PubMed  CAS  Google Scholar 

  • Collinge J, Clarke A (2007) A general model of prion strains and their pathogenicity. Science 318:930–936

    Article  PubMed  CAS  Google Scholar 

  • Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H et al (2006) Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442:920–924

    Article  PubMed  CAS  Google Scholar 

  • Dal Canto MC, Gurney ME (1994) Development of central nervous system pathology in a murine transgenic model of human amyotrophic lateral sclerosis. Am J Pathol 145:1271–1279

    PubMed  CAS  Google Scholar 

  • Danzer KM, Krebs SK, Wolff M, Birk G, Hengerer B (2009) Seeding induced by alpha-synuclein oligomers provides evidence for spreading of alpha-synuclein pathology. J Neurochem 111:192–203

    Article  PubMed  CAS  Google Scholar 

  • Fraser H, Dickinson AG (1973) Scrapie in mice. Agent-strain differences in the distribution and intensity of grey matter vacuolation. J Comp Pathol 83:29–40

    Article  PubMed  CAS  Google Scholar 

  • Frost B, Jacks RL, Diamond MI (2009) Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem 284:12845–12852

    Article  PubMed  CAS  Google Scholar 

  • Georgiou N, Bradshaw JL, Chiu E, Tudor A, O’Gorman L et al (1999) Differential clinical and motor control function in a pair of monozygotic twins with Huntington’s disease. Mov Disord 14:320–325

    Article  PubMed  CAS  Google Scholar 

  • Ghaemmaghami S, Phuan PW, Perkins B, Ullman J, May BC et al (2007) Cell division modulates prion accumulation in cultured cells. Proc Natl Acad Sci USA 104:17971–17976

    Article  PubMed  CAS  Google Scholar 

  • Ghaemmaghami S, Ahn M, Lessard P, Giles K, Legname G et al (2009) Continuous quinacrine treatment results in the formation of drug-resistant prions. PLoS Pathog 5:e1000673

    Article  PubMed  Google Scholar 

  • Gibb SL, Boston-Howes W, Lavina ZS, Gustincich S, Brown RH et al (2007) A caspase-3-cleaved fragment of the glial glutamate transporter EAAT2 is sumoylated and targeted to promyelocytic leukemia nuclear bodies in mutant SOD1-linked amyotrophic lateral sclerosis. J Biol Chem 282:32480–32490

    Article  PubMed  CAS  Google Scholar 

  • Gomez-Esteban JC, Lezcano E, Zarranz JJ, Velasco F, Garamendi I et al (2007) Monozygotic twins suffering from Huntington’s disease show different cognitive and behavioural symptoms. Eur Neurol 57:26–30

    Article  PubMed  CAS  Google Scholar 

  • Gros-Louis F, Gaspar C, Rouleau GA (2006) Genetics of familial and sporadic amyotrophic lateral sclerosis. Biochim Biophys Acta 1762:956–972

    PubMed  CAS  Google Scholar 

  • Hamasaki S, Shirabe S, Tsuda R, Yoshimura T, Nakamura T et al (1998) Discordant Gerstmann-Straussler-Scheinker disease in monozygotic twins. Lancet 352:1358–1359

    Article  PubMed  CAS  Google Scholar 

  • Hardy J (2005) Expression of normal sequence pathogenic proteins for neurodegenerative disease contributes to disease risk: ‘permissive templating’ as a general mechanism underlying neurodegeneration. Biochem Soc Trans 33:578–581

    Article  PubMed  CAS  Google Scholar 

  • Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A et al (2009) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet 41:1088–1093

    Article  PubMed  CAS  Google Scholar 

  • Hill AF, Joiner S, Beck J, Campbell TA, Dickinson A et al (2006) Distinct glycoform ratios of protease resistant prion protein associated with PRNP point mutations. Brain 129:676–685

    Article  PubMed  Google Scholar 

  • Julius C, Hutter G, Wagner U, Seeger H, Kana V et al (2008) Transcriptional stability of cultured cells upon prion infection. J Mol Biol 375:1222–1233

    Article  PubMed  CAS  Google Scholar 

  • Kabashi E, Valdmanis PN, Dion P, Rouleau GA (2007) Oxidized/misfolded superoxide dismutase-1: the cause of all amyotrophic lateral sclerosis? Ann Neurol 62:553–559

    Article  PubMed  CAS  Google Scholar 

  • Kim J, Inoue K, Ishii J, Vanti WB, Voronov SV et al (2007) A microRNA feedback circuit in midbrain dopamine neurons. Science 317:1220–1224

    Article  PubMed  CAS  Google Scholar 

  • Kovacs GG, Puopolo M, Ladogana A, Pocchiari M, Budka H et al (2005) Genetic prion disease: the EUROCJD experience. Hum Genet 118(2):166–174

    Article  PubMed  CAS  Google Scholar 

  • Larner AJ, Doran M (2006) Clinical phenotypic heterogeneity of Alzheimer’s disease associated with mutations of the presenilin-1 gene. J Neurol 253:39–158

    Article  Google Scholar 

  • Li J, Englund E, Holton JL, Soulet D, Hagell P et al (2008) Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat Med 14:501–503

    Article  PubMed  CAS  Google Scholar 

  • Li J, Browning S, Mahal SP, Oelschlegel AM, Weissmann C (2010) Darwinian evolution of prions in cell culture. Proc Natl Acad Sci USA 327:869–872

    CAS  Google Scholar 

  • Lloyd S, Linehan J, Desbruslais M, Joiner S, Buckell J et al (2004) Characterization of two distinct prion strains derived from bovine spongiform encephalopathy transmissions to inbred mice. J Gen Virol 85:2471–2478

    Article  PubMed  CAS  Google Scholar 

  • Mahal SP, Baker CA, Demczyk CA, Smith EW, Julius C et al (2007) Prion strain discrimination in cell culture: the cell panel assay. Proc Natl Acad Sci U S A 104:20908–20913

    Article  PubMed  CAS  Google Scholar 

  • Mead S, Poulter M, Beck J, Webb T, Campbell T et al (2006) Inherited prion disease with six octapeptide repeat insertional mutation–molecular analysis of phenotypic heterogeneity. Brain 129:2297–2317

    Article  PubMed  Google Scholar 

  • Mead S, Webb TE, Campbell TA, Beck J, Linehan J et al (2007) Inherited prion disease with 5-OPRI: phenotype modification by repeat length and codon 129. Neurology 69:730–738

    Article  PubMed  CAS  Google Scholar 

  • Meyer-Luehmann M, Coomaraswamy J, Bolmont T, Kaeser S, Schaefer C et al (2006) Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science 313:1781–1784

    Article  PubMed  CAS  Google Scholar 

  • Morris HR, Gibb G, Katzenschlager R, Wood NW, Hanger DP et al (2002) Pathological, clinical and genetic heterogeneity in progressive supranuclear palsy. Brain 125:969–975

    Article  PubMed  CAS  Google Scholar 

  • Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133

    Article  PubMed  CAS  Google Scholar 

  • Orrell RW, Habgood JJ, Malaspina A, Mitchell J, Greenwood J et al (1999) Clinical characteristics of SOD1 gene mutations in UK families with ALS. J Neurol Sci 169:56–60

    Article  PubMed  CAS  Google Scholar 

  • Owen F, Poulter M, Lofthouse R, Collinge J, Crow TJ et al (1989) Insertion in prion protein gene in familial Creutzfeldt-Jakob disease. Lancet 1:51–52

    Article  PubMed  CAS  Google Scholar 

  • Parchi P, Castellani R, Capellari S, Ghetti B, Young K et al (1996) Molecular basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease. Ann Neurol 39:669–680

    Article  Google Scholar 

  • Parchi P, Chen SG, Brown P, Zou W, Capellari S et al (1998) Different patterns of truncated prion protein fragments correlate with distinct phenotypes in P102L Gerstmann-Sträussler-Scheinker disease. Proc Natl Acad Sci USA 95:8322–8327

    Article  PubMed  CAS  Google Scholar 

  • Petkova AT, Leapman RD, Guo Z, Yau WM, Mattson MP et al (2005) Self-propagating, molecular-level polymorphism in Alzheimer’s beta-amyloid fibrils. Science 307:262–265

    Article  PubMed  CAS  Google Scholar 

  • Prusiner SB (1982) Novel proteinaceous infectious particles cause scrapie. Science 216:136–144

    Article  PubMed  CAS  Google Scholar 

  • Puls I, Jonnakuty C, LaMonte BH, Holzbaur ELF, Tokito M et al (2003) Mutant dynactin in motor neuron disease. Nat Genet 33:455–456

    Article  PubMed  CAS  Google Scholar 

  • Ravits JM, La Spada AR (2009) ALS motor phenotype heterogeneity, focality, and spread: deconstructing motor neuron degeneration. Neurology 73:805–811

    Article  PubMed  Google Scholar 

  • Reid E, Kloos M, Ashley-Koch A, Hughes L, Bevan S et al (2002) A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10). Am J Hum Genet 71:1189–1194

    Article  PubMed  CAS  Google Scholar 

  • Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P et al (1993) Mutations in Cu/An superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362:59–62

    Article  PubMed  CAS  Google Scholar 

  • Schott JM, Ridha BH, Crutch SJ, Healy DG, Uphill JB et al (2006) Apolipoprotein E genotype modifies the phenotype of Alzheimer disease. Arch Neurol 63:155–156

    Article  PubMed  Google Scholar 

  • Simpson CL, Al Chalabi A (2006) Amyotrophic lateral sclerosis as a complex genetic disease. Biochim Biophys Acta 1762:973–985

    PubMed  CAS  Google Scholar 

  • Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C et al (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319:1668–1672

    Article  PubMed  CAS  Google Scholar 

  • Tanaka M, Collins SR, Toyama BH, Weissman JS (2006) The physical basis of how prion conformations determine strain phenotypes. Nature 442:585–589

    Article  PubMed  CAS  Google Scholar 

  • Urushitani M, Sik A, Sakurai T, Nukina N, Takahashi R et al (2006) Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic lateral sclerosis. Nat Neurosci 9:108–118

    Article  PubMed  CAS  Google Scholar 

  • Van Damme P, Van Den Bosch L, Van Houtte E, Callewaert G, Robberecht W (2002) GluR2-dependent properties of AMPA receptors determine the selective vulnerability of motor neurons to excitotoxicity. J Neurophysiol 88:1279–1287

    PubMed  Google Scholar 

  • Vance C, Rogelj B, Hortobagyi T, De Vos KJ, Nishimura AL et al (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323:1208–1211

    Article  PubMed  CAS  Google Scholar 

  • Verhoeven K, De Jonghe D, Coen K, Verpoorten N, Auer-Grumbach M et al (2003) Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot-Marie-Tooth type 2B neuropathy. Am J Hum Genet 72:722–727

    Article  PubMed  CAS  Google Scholar 

  • Wadsworth JD, Hill AF, Beck JA, Collinge J (2003) Molecular and clinical classification of human prion disease. Br Med Bull 66:241–254

    Article  PubMed  CAS  Google Scholar 

  • Wadsworth JD, Joiner S, Linehan J, Cooper S, Powell C et al (2006) Phenotypic heterogeneity in inherited prion disease (P102L) is associated with differential propagation of protease-resistant wild-type and mutant prion protein. Brain 129:1557–1569

    Article  PubMed  Google Scholar 

  • Webb T, Poulter M, Beck J, Uphill J, Adamson G et al (2008) Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series. Brain 131:2632–2646

    Article  PubMed  CAS  Google Scholar 

  • Webb T, Mead S, Beck J, Uphill J, Pal S et al (2009) Seven year discordance in age at onset in monozygotic twins with inherited prion disease (P102L). Neuropathol Appl Neurobiol 35(4):427–432

    Article  PubMed  CAS  Google Scholar 

  • Wickner RB, Edskes HK, Shewmaker F, Nakayashiki T (2007) Prions of fungi: inherited structures and biological roles. Nat Rev Microbiol 5:611–618

    Article  PubMed  CAS  Google Scholar 

  • Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D et al (2001) Loss of huntingtin-mediated BDNF gene transcription in Huntington’s disease. Science 293:493–498

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Ray Young assisted with figure design and artwork. We are grateful to Dr. Jonathan Wadsworth and Dr. Adrian Isaacs for critical review. Simon Mead is funded by the Medical Research Council. This work was supported by the Ipsen Fund, the UK Motor Neurone Disease Association, the Research Advisory Board of St. Bartholomew’s and the Royal London Charitable Foundation (RAB04/F7), and the UK Medical Research Council.

Disclosures

None.

Author information

Authors and Affiliations

  1. Department of Neurodegenerative Disease, University College London, Queen Square, London, WC1N 3BG, UK

    James C. Stevens, Elizabeth M. C. Fisher & Simon Mead

  2. MRC Prion Unit, Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK

    Simon Mead

Authors
  1. James C. Stevens
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elizabeth M. C. Fisher
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Simon Mead
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Simon Mead.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stevens, J.C., Fisher, E.M.C. & Mead, S. How does the genetic assassin select its neuronal target?. Mamm Genome 22, 139–147 (2011). https://doi.org/10.1007/s00335-011-9319-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00335-011-9319-5

Keywords

Search

Navigation