Genetic risk factor for Alzheimer disease

Summaries of newsworthy papers from Nature and the Nature Research Journals that will be published online on 14 January 2007. Sizing up stem cells, Maintaining immune regulation, and Getting things into cells with the aid of small molecules.


For papers that will be published online on 14 January 2007

This press release is copyrighted to the Nature journals mentioned below.

This press release contains:
• Summaries of newsworthy papers:
Genetic risk factor for Alzheimer disease – Nature Genetics
Sizing up stem cells – Nature Genetics
Maintaining immune regulation – Nature Immunology and Nature
Getting things into cells with the aid of small molecules – Nature Methods
• Mention of papers to be published at the same time with the same embargo
• Geographical listing of authors

PDFs of all the papers mentioned on this release can be found in the relevant journal’s section of Press contacts for the Nature journals are listed at the end of this release.

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*********************NATURE GENETICS ***********************

[1] Genetic risk factor for Alzheimer disease
DOI: 10.1038/ng1943

Individuals with particular variants of the gene SORL1 have a modestly elevated risk of late-onset Alzheimer disease, according to a study to be published in the February issue of Nature Genetics. If confirmed in additional studies, SORL1 represents the second genetic risk factor for this most common form of the disease, usually diagnosed after age 65.

The key event in the progression of Alzheimer disease is the generation of A-beta peptide from a protein called amyloid precursor protein (APP). The A-beta peptide is toxic to neurons, and is thought to be a trigger for the neurodegeneration observed in the disease. Previous research suggests that brain tissue from individuals with the disease had reduced levels of several proteins that modulate the processing of APP into A-beta, but it was unclear whether these were causal changes.

Peter St. George-Hyslop and colleagues searched for variants in genes encoding several APP-processing proteins that might be associated with Alzheimer disease. By analyzing six different populations of individuals from different ethnic backgrounds, they identified two clusters of variants in SORL1 that were significantly overrepresented in those with the disease.

In addition to these genetic data, the authors provided preliminary evidence that individuals with Alzheimer disease tend to have lower levels of SORL1 in blood cells. Moreover, they show that experimentally reducing the level of SORL1 in cultured cells promotes the production of A-beta peptide, suggesting a potential mechanism whereby these SORL1 variants increase the risk of neurodegeneration.

Author contacts:
Peter St. George-Hyslop (University of Toronto, Ontario, Canada)
Tel: +1 416 978 7460; E-mail: [email protected]

Lindsay Farrer (Boston University School of Medicine, Boston, MA, USA)
Tel: +1 617 638 5393; E-mail: [email protected]

Richard Mayeux (Columbia University College of Physicians and Surgeons, New York, NY, USA)
Tel: +1 212 305 2391; E-mail: [email protected]

Steven Younkin (Mayo Clinic, Jacksonville, FL, USA)
Tel: +1 904 953 7356; E-mail: [email protected]

[2] Sizing up stem cells
DOI: 10.1038/ng1938

A gene called latexin has a significant effect on the blood stem cell population in young mice, according to a study to be published in the February issue of Nature Genetics. This finding provides insights into how the population of stem cells is regulated, which could have implications for stem cell–based clinical therapies.

Twenty-five years ago, Gary Van Zant and colleagues showed that the size of the blood stem cell population can vary in different strains of mice, with a strain called D2 typically having at least three times as many blood stem cells as a strain called B6. They subsequently narrowed down the genetic contribution to this variation to regions on three different chromosomes, and now report the identification of the first gene, latexin. Here they experimentally tested the role of latexin by infecting cultured bone marrow cells with a virus promoting the expression of high levels of latexin. They transplanted these cells into recipient mice and found that overexpression of latexin had the effect of reducing the number of blood stem cells, suggesting that it acts as an inhibitor of stem cell expansion.

Author contact:
Gary Van Zant (University of Kentucky, Lexington, KY, USA)
Tel: +1 859 323 5719; E-mail: [email protected]

Other papers from Nature Genetics to be published online at the same time and with the same embargo

[3] A multistep epigenetic switch enables the stable inheritance of DNA methylation states
DOI: 10.1038/ng1956

[4] Zebrafish miR-214 modulates Hedgehog signaling to specify muscle cell fate
DOI: 10.1038/ng1953

******************* NATURE IMMUNOLOGY *****************

[5] Maintaining immune regulation
DOI: 10.1038/ni1437

Constant expression of a single protein, Foxp3, is essential to maintain the identity and character of regulatory T (Treg) cells, according to a paper appearing in the March issue of Nature Immunology.

Treg cells are needed to suppress autoimmune diseases. Although Foxp3 expression is required for the production of these cells, it is unknown whether continuous expression of Foxp3 is critical for maintaining the suppressive function of Treg cells.

Alexander Rudensky and colleagues used a clever strategy to test the requirement for continuous Foxp3 expression by deleting ‘Foxp3’ from mature Treg cells. These Foxp3-deficient cells lost hallmark Treg features and, unlike normal Treg cells, failed to suppress auto-aggressive T cells and the development of autoimmunity in mice. Precisely how Foxp3 persistence maintains the Treg ‘identity’ remains for future investigation.

Author contact:
Alexander Rudensky, University of Washington, Seattle, WA, USA)
Tel: +1 206 685 7644; E-mail: [email protected]

This paper is linked to the following two Nature papers:

[6] Foxp3-dependent programme of regulatory T-cell differentiation
DOI: 10.1038/nature05543

[7] Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression
DOI: 10.1038/nature05479

****************** NATURE METHODS ********************

[8] Getting things into cells with the aid of small molecules
DOI: 10.1038/nmeth997

Small molecules can be linked to much larger cargoes and deliver them into a variety of cell types, according to an article to be published online this week in Nature Methods.

Cells tightly regulate which molecules they allow to enter, but it is often useful for research or therapeutic purposes to induce the uptake of bulky proteins or hydrophilic molecules, which are normally denied entry. It has been known for some time that certain short alpha-helical peptides can permeate the cell membrane; however, their application is limited by high cost and the potential for biodegradation. David Selwood and colleagues now overcome these obstacles by designing small molecules based on this alpha-helical structure. These new small molecule carriers efficiently transport other small molecules such as dyes and proteins into several different cell types.

With this report, Selwood and colleagues have introduced a novel strategy for intracellular delivery that could have wide-reaching implications for both basic research and pharmacology, including drug delivery and gene therapy. In an accompanying News & Views piece, Alain Prochiantz notes that this work may lead to the “the discovery of [other small molecule] mimics and to the development of efficient strategies to reach intracellular targets.”

Author contact:
David Selwood (University College London, UK)
Tel: +44 207 679 6716; E-mail: [email protected]

Additional contact for comment on paper:
Alain Prochiantz (Ecole Normale Supérieure, France)
Tel: +33 1 44 32 37 12; E-mail: [email protected]

Other papers from Nature Methods to be published online at the same time and with the same embargo:

[9] Transposon-tagged mutagenesis in the rat
DOI: 10.1038/nmeth1002


Items from other Nature journals to be published online at the same time and with the same embargo:

Nature (

[10] Basis for a ubiquitin-like protein thioester switch toggling E1–E2 affinity
DOI: 10.1038/nature05490


[11] Bioinformatic discovery of novel bioactive peptides
DOI: 10.1038/nchembio854

[12] Two interconverting Fe(iv) intermediates in aliphatic chlorination by the halogenase CytC3
DOI: 10.1038/nchembio856

Nature PHYSICS (

[13] Experimental entanglement of six photons in graph states
DOI: 10.1038/nphys507

[14] Quantum non-demolition measurement of a superconducting two-level system
DOI: 10.1038/nphys509


[15] High-throughput mapping of the chromatin structure of human promoters
DOI: 10.1038/nbt1279

[16] Complementation of placental defects and embryonic lethality by trophoblast-specific lentiviral gene transfer
DOI: 10.1038/nbt1280


[17] Hippocampal cellular and network activity in freely moving echolocating bats
DOI: 10.1038/nn1829

[18] Synaptic vesicles recycling spontaneously and during activity belong to the same vesicle pool
DOI: 10.1038/nn1831

[19] Sharpened cochlear tuning in a mouse with a genetically modified tectorial membrane
DOI: 10.1038/nn1828

[20] Notch signal organizes the Drosophila olfactory circuitry by diversifying the sensory neuronal lineages
DOI: 10.1038/nn1832

[21] Presynaptic Ca2+ buffers control the strength of a fast post-tetanic hyperpolarization mediated by the a3 Na+/K+-ATPase
DOI: 10.1038/nn1839

[22] Drosophila spichthyin inhibits BMP signaling and regulates synaptic growth and axonal microtubules
DOI: 10.1038/nn1841


[23] Chemotaxis in shallow gradients is mediated independently of PtdIns 3-kinase by biased choices between random protrusions
DOI: 10.1038/ncb1536

[24] Interaction between beta-catenin and HIF-1 promotes cellular adaptation to hypoxia
DOI: 10.1038/ncb1534

[25] Cortical microtubule arrays undergo rotary movements in Arabidopsis hypocotyl epidermal cells
DOI: 10.1038/ncb1533


[26] Adenovirus type 11 binding alters the conformation of its receptor CD46
DOI: 10.1038/nsmb1190

[27] A topological mechanism for TRF2-enhanced strand invasion
DOI: 10.1038/nsmb1192

[28] Crystal structure of a complete ternary complex of TCR, superantigen and peptide-MHC
DOI: 10.1038/nsmb1193

[29] A general amphipathic alpha-helical motif for sensing membrane curvature
DOI: 10.1038/nsmb1194

[30] The guanylate kinase domain of the MAGUK PSD-95 binds dynamically to a conserved motif in MAP1a
DOI: 10.1038/nsmb1195


This paper is to be published electronically on Nature Genetics’s website on 09 January 2007 so is not under embargo. We have included it on this release to avoid multiple mailings. All other papers on this release are embargoed for 1800 GMT Sunday 14 January

[31] A stem cell–like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing
DOI: 10.1038/ng1972


The following list of places refers to the whereabouts of authors on the papers numbered in this release. The listing may be for an author's main affiliation, or for a place where they are working temporarily. Please see the PDF of the paper for full details.

Innsbruck: 13
Vienna: 31

Montreal: 28
Toronto: 1

Anhui: 13
Hong Kong: 1

Lyon: 27
Paris: 14
Valbonne: 29

Berlin: 1
Frankfurt am Main: 30
Goettingen: 18
Hamburg: 1
Heidelberg: 13
Tubingen: 26

Dublin: 11

Haifa: 1

Florence: 1
Lamezia Terme: 1
Trieste : 27
Turin: 1

Chiba: 1
Hokkaido: 20
Hyogo: 20
Kanagawa: 14
Mie: 16
Osaka: 9, 16
Sapporo: 9
Tochigi: 9
Tokyo: 20

Delft: 14

Madrid: 26

Lausanne: 27

Birmingham: 23
Brighton: 19
Bristol: 24
Cambridge: 8, 22
London: 8
Norwich: 25

Little Rock: 21
Berkeley: 3, 10
La Jolla: 16
San Francisco: 30
New Haven: 7
Jacksonville: 1
Miami: 1
Urbana: 28
Indianapolis: 30
Lexington: 2
Baltimore: 31
Bethesda: 6
College Park: 17
Boston: 1, 10, 12, 15
Cambridge: 3, 29
Rochester: 1
New Mexico
Albany: 28
New York
New York: 1
Cincinnati: 2
Cleveland: 1
Portland: 21
University Park: 12
Memphis: 10
Nashville: 4
Seattle: 5, 6


For media inquiries relating to embargo policy for all the Nature Research Journals:

Katherine Anderson (Nature London)
Tel: +44 20 7843 4502; E-mail: [email protected]

Ruth Francis (Senior Press Officer, Nature, London)
Tel: +44 20 7843 4562; E-mail: [email protected]

For media inquiries relating to editorial content/policy for the Nature Research Journals, please contact the journals individually:

Nature Biotechnology (New York)
Peter Hare
Tel: +1 212 726 9284; E-mail: [email protected]

Nature Cell Biology (London)
Bernd Pulverer
Tel: +44 20 7843 4892; E-mail: [email protected]

Nature Chemical Biology (Boston)
Andrea Garvey
Tel: +1 617 475 9241, E-mail: [email protected]

Nature Genetics (New York)
Orli Bahcall
Tel: +1 212 726 9311; E-mail: [email protected]

Nature Immunology (New York)
Laurie Dempsey
Tel: +1 212 726 9372; E-mail: [email protected]

Nature Methods (New York)
Allison Doerr
Tel: +1 212 726 9393; E-mail: [email protected]

Nature Neuroscience (New York)
Sandra Aamodt (based in California)
Tel: +1 530 795 3256; E-mail: [email protected]

Nature Physics (London)
Alison Wright
Tel: +44 20 7843 4555; E-mail: [email protected]

Nature Structural & Molecular Biology (New York)
Michelle Montoya
Tel: +1 212 726 9326; E-mail: [email protected]

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Published: 14 Jan 2007

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