Skip to main content
SpringerLink
Log in

RNA regulation in Neurodegeneration and Cancer

  • Chapter
  • First Online:
Two Faces of Evil: Cancer and Neurodegeneration

Part of the book series: Research and Perspectives in Alzheimer's Disease ((ALZHEIMER))

  • 538 Accesses

Abstract

The paraneoplastic neurologic diseases are a set of brain degenerations that develop in the setting of occult cancer. These disorders arise when common cancers express brain proteins, triggering an anti-tumor immune response and tumor immunity. Studies of the nature of these brain-cancer proteins has revealed a new world of neuron-specific RNA binding proteins whose functions may be co-opted by tumor cells. The interest in their function has spawned the development of new methods and strategies to understand RNA-protein regulation in living tissues. These approaches, and the new biology they reveal, are discussed here.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Albert ML, Darnell RB (2004) Paraneoplastic neurological degenerations: keys to tumour immunity. Nat Rev Cancer 4:36–44

    Article  PubMed  CAS  Google Scholar 

  • Albert ML, Darnell JC, Bender A, Francisco LM, Bhardwaj N, Darnell RB (1998) Tumor-specific killer cells in paraneoplastic cerebellar degeneration. Nat Med 4:1321–1324

    Article  PubMed  CAS  Google Scholar 

  • Albert ML, Austin LM, Darnell RB (2000) Detection and treatment of activated T cells in the cerebrospinal fluid of patients with paraneoplastic cerebellar degeneration. [see comments]. Ann Neurol 47:9–17

    Article  PubMed  CAS  Google Scholar 

  • Buckanovich RJ, Darnell RB (1997) The neuronal RNA binding protein Nova-1 recognizes specific RNA targets in vitro and in vivo. Mol Cell Biol 17:3194–3201

    PubMed  CAS  Google Scholar 

  • Buckanovich RJ, Posner JB, Darnell RB (1993) Nova, the paraneoplastic Ri antigen, is homologous to an RNA-binding protein and is specifically expressed in the developing motor system. Neuron 11:657–672

    Article  PubMed  CAS  Google Scholar 

  • Buckanovich RJ, Yang YY, Darnell RB (1996) The onconeural antigen Nova-1 is a neuron-specific RNA-binding protein, the activity of which is inhibited by paraneoplastic antibodies. J Neurosci 16:1114–1122

    PubMed  CAS  Google Scholar 

  • Chi SW, Zang JB, Mele A, Darnell RB (2009) Argonaute HITS-CLIP decodes microRNA-mRNA interaction maps. Nature 460:479–486

    PubMed  CAS  Google Scholar 

  • Darnell RB (1996) Onconeural antigens and the paraneoplastic neurologic disorders: at the intersection of cancer, immunity and the brain. Proc Natl Acad Sci USA 93:4529–4536

    Article  PubMed  CAS  Google Scholar 

  • Darnell RB (2006) Developing global insight into RNA regulation. Cold Spring Harb Symp Quant Biol 71:321–327

    Article  PubMed  CAS  Google Scholar 

  • Darnell RB (2010) HITS-CLIP: panoramic views of protein-RNA regulation in living cells. Wiley Interdiscip Rev RNA (in press)

    Google Scholar 

  • Darnell RB, Posner JB (2006) Paraneoplastic syndromes affecting the nervous system. Semin Oncol 33:270–298

    Article  PubMed  Google Scholar 

  • Darnell RB, Furneaux H, Posner JB (1989) Characterization of antigens bound by CSF and serum of a patient with cerebellar degeneration: co-expression in Purkinje cells and tumor lines of neuroectodermal origin. Neurology 39:385

    Article  Google Scholar 

  • Darnell RB, Furneaux HM, Posner JB (1991) Antiserum from a patient with cerebellar degeneration identifies a novel protein in Purkinje cells, cortical neurons, and neuroectodermal tumors. J Neurosci 11:1224–1230

    PubMed  CAS  Google Scholar 

  • Dredge BK, Darnell RB (2003) Nova regulates GABA(A) receptor gamma2 alternative splicing via a distal downstream UCAU-rich intronic splicing enhancer. Mol Cell Biol 23:4687–4700

    Article  PubMed  CAS  Google Scholar 

  • Dredge BK, Polydorides AD, Darnell RB (2001) The splice of life: alternative splicing and neurological disease. Nat Rev Neurosci 2:43–50

    Article  PubMed  CAS  Google Scholar 

  • Dredge BK, Stefani G, Engelhard CC, Darnell RB (2005) Nova autoregulation reveals dual functions in neuronal splicing. EMBO J 24:1608–1620

    Article  PubMed  CAS  Google Scholar 

  • Graus F, Cordon-Cardo C, Posner JB (1985) Neuronal antinuclear antibody in sensory neuronopathy from lung cancer. Neurology 35:538–543

    Article  PubMed  CAS  Google Scholar 

  • Green R, Ellington AD, Bartel DP, Szostak JW (1991) In vitro genetic analysis: selection and amplification of rare functional nucleic acids. Meth Compan Methods Enzymol 2:75–86

    Article  CAS  Google Scholar 

  • Hafner M, Landthaler M, Burger L, Khorshid M, Hausser J, Berninger P, Rothballer A, Ascano MJ, Jungkamp AC, Munschauer M, Ulrich A, Wardle GS, Dewell S, Zavolan M, Tuschl T (2010) Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP. Cell 141:129–141

    Article  PubMed  CAS  Google Scholar 

  • Hinman MN, Lou H (2008) Diverse molecular functions of Hu proteins. Cell Mol Life Sci 65:3168–3181

    Article  PubMed  CAS  Google Scholar 

  • Jensen KB, Musunuru K, Lewis HA, Burley SK, Darnell RB (2000) The tetranucleotide UCAY directs the specific recognition of RNA by the Nova K-homology 3 domain. Proc Natl Acad Sci USA 97:5740–5745

    Article  PubMed  CAS  Google Scholar 

  • Konig J, Zarnack K, Rot G, Curk T, Kayikci M, Blaz Z, Turner DJ, Luscombe NM, Ule J (2010) iCLIP reveals the function of hnRNP particles in splicing at individual nucleotide resolution. Nat Struct Mol Biol 17:909–915

    Article  PubMed  Google Scholar 

  • Lewis HA, Musunuru K, Jensen KB, Edo C, Chen H, Darnell RB, Burley SK (2000) Sequence-specific RNA binding by a Nova KH domain: implications for paraneoplastic disease and the fragile X syndrome. Cell 100:323–332

    Article  PubMed  CAS  Google Scholar 

  • Licatalosi DD, Darnell RB (2006) Splicing regulation in neurologic disease. Neuron 52:93–101

    Article  PubMed  CAS  Google Scholar 

  • Licatalosi DD, Darnell RB (2010) RNA processing and its regulation: global insights into biological networks. Nat Rev Genet 11:75–87

    Article  PubMed  CAS  Google Scholar 

  • Licatalosi DD, Mele A, Fak JJ, Ule J, Kayikci M, Chi SW, Clark TA, Schweitzer AC, Blume JE, Wang X, Darnell JC, Darnell RB (2008) HITS-CLIP yields genome-wide insights into brain alternative RNA processing. Nature 456:464–469

    Article  PubMed  CAS  Google Scholar 

  • McKeever MO, Darnell RB (1992) NAP, a human cerebellar degeneration antigen, is a novel, neuron specific, adaptin family member. Soc Neurosci Abstr 18:1092

    Google Scholar 

  • Musunuru K, Darnell RB (2001) Paraneoplastic neurologic disease antigens: RNA-binding proteins and signaling proteins in neuronal degeneration. Annu Rev Neurosci 24:239–262

    Article  PubMed  CAS  Google Scholar 

  • Newman LS, McKeever MO, Okano HJ, Darnell RB (1995) β-NAP, a cerebellar degeneration antigen, is a neuron-specific vesicle coat protein. Cell 82:773–783

    Article  PubMed  CAS  Google Scholar 

  • Roberts WK, Darnell RB (2004) Neuroimmunology of the paraneoplastic neurological degenerations. Curr Opin Immunol 16:616–622

    Article  PubMed  CAS  Google Scholar 

  • Sanford JR, Wang X, Mort M, Vanduyn N, Cooper DN, Mooney SD, Edenberg HJ, Liu Y (2009) Splicing factor SFRS1 recognizes a functionally diverse landscape of RNA transcripts. Genome Res 19:381–394

    Article  PubMed  CAS  Google Scholar 

  • Santomasso BD, Roberts WK, Thomas A, Williams T, Blachere NE, Dudley ME, Houghton AN, Posner JB, Darnell RB (2007) A T-cell receptor associated with naturally occurring human tumor immunity. Proc Natl Acad Sci USA 104:19073–19078

    Article  PubMed  CAS  Google Scholar 

  • Szabo A, Dalmau J, Manley G, Rosenfeld M, Wong E, Henson J, Posner JB, Furneaux HM (1991) HuD, a paraneoplastic encephalomyelitis antigen contains RNA-binding domains and is homologous to Elav and sex lethal. Cell 67:325–333

    Article  PubMed  CAS  Google Scholar 

  • Szostak JW, Ellington AD (1993) In vitro selection of functional RNA sequences. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY

    Google Scholar 

  • Ule J, Jensen KB, Ruggiu M, Mele A, Ule A, Darnell RB (2003) CLIP identifies Nova-regulated RNA networks in the brain. Science 302:1212–1215

    Article  PubMed  CAS  Google Scholar 

  • Ule J, Ule A, Spencer J, Williams A, Hu JS, Cline M, Wang H, Clark T, Fraser C, Ruggiu M, Zeeberg BR, Kane D, Weinstein JN, Blume J, Darnell RB (2005) Nova regulates brain-specific splicing to shape the synapse. Nat Genet 37:844–852

    Article  PubMed  CAS  Google Scholar 

  • Ule J, Stefani G, Mele A, Ruggiu M, Wang X, Taneri B, Gaasterland T, Blencowe BJ, Darnell RB (2006) An RNA map predicting Nova-dependent splicing regulation. Nature 444:580–586

    Article  PubMed  CAS  Google Scholar 

  • Xu M, Medvedev S, Yang J, Hecht NB (2009) MIWI-independent small RNAs (MSY-RNAs) bind to the RNA-binding protein, MSY2, in male germ cells. Proc Natl Acad Sci USA 106:12371–12376

    Article  PubMed  CAS  Google Scholar 

  • Xue Y, Zhou Y, Wu T, Zhu T, Ji X, Kwon YS, Zhang C, Yeo G, Black DL, Sun H, Fu XD, Zhang Y (2009) Genome-wide analysis of PTB-RNA interactions reveals a strategy used by the general splicing repressor to modulate exon inclusion or skipping. Mol Cell 36:996–1006

    Article  PubMed  CAS  Google Scholar 

  • Yang YY, Yin GL, Darnell RB (1998) The neuronal RNA-binding protein Nova-2 is implicated as the autoantigen targeted in POMA patients with dementia. Proc Natl Acad Sci USA 95:13254–13259

    Article  PubMed  CAS  Google Scholar 

  • Yeo GW, Coufal NG, Liang TY, Peng GE, Fu XD, Gage FH (2009) An RNA code for the FOX2 splicing regulator revealed by mapping RNA-protein interactions in stem cells. Nat Struct Mol Biol 16:130–137

    Article  PubMed  CAS  Google Scholar 

  • Zhang C, Frias MA, Mele A, Licatalosi D, Darnell RB (2010) Integrative modeling defines a comprehensive splicing-regulatory network and its combinatorial controls. Science 329:439–443

    Article  PubMed  CAS  Google Scholar 

  • Zisoulis DG, Lovci MT, Wilbert ML, Hutt KR, Liang TY, Pasquinelli AE, Yeo GW (2010) Comprehensive discovery of endogenous Argonaute binding sites in Caenorhabditis elegans. Nat Struct Mol Biol 17:173–179

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work is an overview of the efforts of a large number of people and their experiments undertaken over the years. While I have tried to cite the efforts of all, I would especially thank Steven Burley, Ron Buckanovich, Jennifer Darnell, Kate Dredge, Lily Jan, Kirk Jensen, Hal Lewis, Aldo Mele, Kiran Musunuru, Giovanni Stefani, Jernej Ule, Donny Licatalosi, Sung-Wook Chi and Chaolin Zhang for major contributions toward developing the key points in the development of the story told here. This work was supported by the NIH (R01 NS34389 and NS40955 to RBD) and the Howard Hughes Medical Institute. RBD is an Investigator of the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

  1. Laboratory of Molecular Neuro-Oncology, Howard Hughes Medical Institute, The Rockefeller University, 226, 1230 York Ave, New York, NY, 10021, USA

    Robert B. Darnell

Authors
  1. Robert B. Darnell
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert B. Darnell .

Editor information

Editors and Affiliations

  1. , Department of Pathology and Laboratory M, The Children's Hospital of Philadelphia, Civic Center Boulevard 3501, Philadelphia, 19104, Pennsylvania, USA

    Thomas Curran

  2. Fondation IPSEN, Quai Georges Gorse 65, Boulogne-Billancourt Cedex, 92650, France

    Yves Christen

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Darnell, R.B. (2011). RNA regulation in Neurodegeneration and Cancer. In: Curran, T., Christen, Y. (eds) Two Faces of Evil: Cancer and Neurodegeneration. Research and Perspectives in Alzheimer's Disease. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-16602-0_9

Download citation

Publish with us

Policies and ethics

Search

Navigation