Article

Functional screening of Alzheimer pathology genome-wide association signals in Drosophila.

Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA.
The American Journal of Human Genetics (Impact Factor: 11.2). 02/2011; 88(2):232-8. DOI: 10.1016/j.ajhg.2011.01.006
Source: PubMed

ABSTRACT We have leveraged a Drosophila model relevant to Alzheimer disease (AD) for functional screening of findings from a genome-wide scan for loci associated with a quantitative measure of AD pathology in humans. In six of the 15 genomic regions evaluated, we successfully identified a causal gene for the association, on the basis of in vivo interactions with the neurotoxicity of Tau, which forms neurofibrillary tangles in AD. Among the top results, rs10845990 within SLC2A14, encoding a glucose transporter, showed evidence of replication for association with AD pathology, and gain and loss of function in glut1, the Drosophila ortholog, was associated with suppression and enhancement of Tau toxicity, respectively. Our strategy of coupling genome-wide association in humans with functional screening in a model organism is likely to be a powerful approach for gene discovery in AD and other complex genetic disorders.

0 Bookmarks
 · 
138 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Amyloid plaques and neurofibrillary tangles (NFTs) are the defining pathological hallmarks of Alzheimer's disease (AD). Increasing the quantity of the O-linked N-acetylglucosamine (O-GlcNAc) post-translation modification of nuclear and cytoplasmic proteins slows neurodegeneration and blocks the formation of NFTs in a tauopathy mouse model. It remains unknown, however, if O-GlcNAc can influence the formation of amyloid plaques in the presence of tau pathology.
    Molecular Neurodegeneration 10/2014; 9(1):42. DOI:10.1186/1750-1326-9-42 · 5.29 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Here, we review the genetic risk factors for late onset Alzheimer’s disease (AD) and their role in AD pathogenesis. Recent advances in our understanding of the human genome, namely technological advances in methods to analyze millions of polymorphisms in thousands of subjects, have revealed new genes associated with AD risk: ABCA7, BIN1, CASS4, CD33, CD2AP, CELF1, CLU, CR1, DSG2, EPHA1, FERMT2, HLA-DRB5-DBR1, INPP5D, MS4A, MEF2C, NME8, PICALM, PTK2B, SLC24H4-RIN3, SORL1, ZCWPW1. Emerging technologies to analyze the entire genome in large datasets have also revealed coding variants that increase AD risk: PLD3 and TREM2. We review the relationship between these AD risk genes and the cellular and neuropathological features of AD. Together, understanding the mechanisms underlying the association of these genes with risk for disease will provide the most meaningful targets for therapeutic development to-date.
    Biological Psychiatry 01/2014; 77(1). DOI:10.1016/j.biopsych.2014.05.006 · 9.47 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The commonest known cause of Parkinson´s disease (PD) is the G2019S mutation of the LRRK2 gene, but this mutation is not sufficient for causing PD, and many carriers of the mutation never develop PD symptoms during life. Differences at the expression level of certain genes, resulting from either genetic variations or environmental interactions, might be one of the mechanisms underlying differential risks for developing both idiopathic and genetic PD. In order to identify genes involved in PD pathogenesis, we compared genome wide gene expression (RNA-seq) in peripheral blood of 20 PD patients carrying the G2019S mutation of the LRRK2 gene, 20 asymptomatic carriers of the mutation, 20 subjects with idiopathic PD, 20 controls and seven PD patients before and after initiating dopaminergic therapy. We identified 13 common genes (ADARB2, CEACAM6, CNTNAP2, COL19A1, DEF4, DRAXIN, FCER2, HBG1, NCAPG2, PVRL2, SLC2A14, SNCA and TCL1B) showing significant differential expression between G2019S-associated PD and asymptomatic carriers and also between idiopathic PD and controls but not between untreated and treated patients. Some of these genes are functionally involved in processes known to be involved in PD pathogenesis, such as Akt signaling, glucose metabolism or immunity. We consider that these genes merit further attention in future studies as potential candidate genes involved in both idiopathic and LRRK2 G2019S-associated forms of PD.
    Neurobiology of Aging 11/2014; DOI:10.1016/j.neurobiolaging.2014.10.039 · 4.85 Impact Factor

Full-text (2 Sources)

Download
7 Downloads
Available from
Dec 11, 2014

Joshua M Shulman