Down syndrome traced to one gene

Down syndrome and other neurodegenerative diseases may be caused by impairments in signaling and transport of neurotrophins, according to two studies released this week in Neuron, challenging the hypothesis that an inadequate supply of these essential brain chemicals is to blame. And for Down syndrome, a condition in which several hundred genes are triplicated due to a trisomy of chromosome 21, one gene associated with Alzheimer's disease may be the chief culprit."You can stop thinking of Down syndrome as this murky area where you'll never discover specific genes that make a difference," said William Mobley of Stanford University, the senior author of the study that focused on Down syndrome.In the study, Mobley and his team, including co-authors Ahmad Salehi and Jean-Dominique Delcroix, linked a brain abnormality found in Down syndrome to the gene for amyloid precursor protein (APP), a protein associated with brain plaques in Alzheimer's disease. To arrive at this finding, Mobley's team worked with mice trisomic for a segment of chromosome 16 that contains homologs of human chromosome 21 genes. In these mouse models of Down syndrome, the ability of cholinergic neurons of the basal forebrain to transport neural growth factor (NGF), a neurotrophin, from the axon to the cell body was only about 10% of that of normal mice. Deprived of the retrograde transport of NGF, the cholinergic neurons in the trisomic mice show significant atrophy, the researchers report.To show that the APP gene was the chief culprit, Mobley's team deleted the extra copy of it in trisomic mice, and this restored NGF transport to more than 50% of the normal level -- even though all the remaining genes on the extra chromosome 16 segment were still present in triplicate. "Getting rid of the extra copy of that one gene makes a lot of difference," Mobley said. "This is a new and significant contribution," said David Patterson of the University of Denver in Colorado, who was not involved in the study. "It gives us an insight into how cholinergic neurons degenerate, and also gives us some potential therapeutic targets."In the -->second study-->, the researchers showed that premature neuronal cell death in trisomic mice could be prevented by restoring normal levels of a Trk receptor for brain-derived neurotrophic factor (BDNF), another neurotrophin. Previously, they had found that in mice with a complete extra copy of chromosome 16, hippocampal neurons die prematurely because they overexpress a truncated form of the TrkB receptor for BDNF, and this reduced the responsiveness of the cells to the molecule. Supplying excess BDNF did not help, but overexpressing the full length TrkB receptor rescued the cells in vitro. In their recent Neuron paper, the researchers show that by deleting one copy of the gene for the truncated isoform, normal BDNF signaling can be restored, and the cells can be rescued in vivo."Our results challenge the notion that neurodegeneration is simply a neurotrophin supply problem," said study author Susan Dorsey of the University of Maryand School of Nursing in Baltimore. "If you can make a modification at the receptor level that makes it more sensitive to the endogenous levels of neurotrophins, you'd have achieved what people have been trying for a decade by giving more neurotrophins," added co-author Lino Tessarollo of the Mouse Cancer Genetics Program at the National Cancer Institute in Frederick, Md."The belief among neuroscientists has been than the neurotrophin ligands are themselves limiting," explained Barbara Hempstead of the Weill Medical College of Cornell University in New York, who was not involved in the study. "The thing that is particularly exciting about this new study is it suggests that the regulation of neurotrophin signaling is a major mechanism by which neuronal cell loss is mediated. It is an elegant use of genetics."Chandra Shekhar cshekhar@the-scientist.comLinks within this articleWilliam Mobley http://mobleylab.stanford.edu/lab_members.htmlA.Salehi et al., "Increased App expression in a mouse model of Down's syndrome disrupts NGF transport and causes cholinergic neuron degeneration," Neuron, July 6, 2006. PM_ID: 16815330.Ahmad Salehi http://mobleylab.stanford.edu/ahmad.htmlJean-Dominique Delcroix http://mobleylab.stanford.edu/jd.htmlM. Anderson, "Amending the amyloid hypothesis," The Scientist, October 25, 2004. http://www.the-scientist.com/article/display/15006/David Patterson http://www.nsm.du.edu/eri/faculty.cfm?ID=dpatter2S.G. Dorsey et al., "In vivo restoration of physiological levels of truncated TrkB.T1 receptor rescues neuronal cell death in a trisomic mouse model," Neuron, July 6, 2006. -->PM_ID: 168153329-->.Susan Dorsey http://nursing.umaryland.edu/faculty/osah/dorsey.htmLino Tessarollo http://ccr.cancer.gov/staff/staff.asp?profileid=5569Barbara L. Hempstead http://www.med.cornell.edu/research/bhempstead/

Down syndrome traced to one gene

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