QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, November 29, 2006, 26(48):12408-12414; doi:10.1523/JNEUROSCI.3372-06.2006

This Article Full Text Full Text (PDF) A correction has been published Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Related articles in J. Neurosci. Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Gavin, B. A. Articles by Supattapone, S. Search for Related Content PubMed PubMed Citation Articles by Gavin, B. A. Articles by Supattapone, S.

 Previous Article  |  Next Article 

Neurobiology of Disease
Accelerated Accumulation of Misfolded Prion Protein and Spongiform Degeneration in a Drosophila Model of Gerstmann–Sträussler–Scheinker Syndrome

Brendan A. Gavin,¹ Maria J. Dolph,¹ Nathan R. Deleault,² James C. Geoghegan,² Vikram Khurana,³ Mel B. Feany,³ Patrick J. Dolph,¹ and Surachai Supattapone²

¹Department of Biology, Dartmouth College, Hanover, New Hampshire 03755, ²Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755, and ³Department of Pathology, Division of Neuropathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115

Correspondence should be addressed to either of the following: Surachai Supattapone, Department of Biochemistry, Dartmouth Medical School, 7200 Vail Building, Hanover, NH 03755, Email: supattapone{at}Dartmouth.edu; or Patrick J. Dolph, Department of Biology, Dartmouth College, Hanover, NH 03755, Email: partick.j.dolph{at}dartmoth.edu

Prion diseases are CNS disorders that can occur in sporadic, infectious, and inherited forms. Although all forms of prion disease are associated with the accumulation of pathogenic conformers of the prion protein, collectively termed PrP^Sc, the mechanisms by which PrP^Sc molecules form and cause neuronal degeneration are unknown. Using the bipartite galactosidase-4–upstream activating sequence expression system, we generated transgenic Drosophila melanogaster heterologously expressing either wild-type (WT) or mutant, disease-associated (P101L) mouse PrP molecules in cholinergic neurons. Transgenic flies expressing neuronal P101L PrP molecules exhibited severe locomotor dysfunction and premature death as larvae and adults. These striking clinical abnormalities were accompanied by age-dependent accumulation of misfolded PrP molecules, intracellular PrP aggregates, and neuronal vacuoles. In contrast, transgenic flies expressing comparable levels of WT PrP displayed no clinical, pathological, or biochemical abnormalities. These results indicate that transgenic Drosophila expressing neuronal P101L PrP specifically exhibit several hallmark features of human Gerstmann–Sträussler–Scheinker (GSS) syndrome. Because the rates of abnormal PrP accumulation and clinical progression are highly accelerated in Drosophila compared with the rates of these processes in rodents or humans, the P101L mutant may be used for future genetic and pharmacologic studies as a novel invertebrate model of GSS.

Key words: prion; Drosophila; Gerstmann–Sträussler–Scheinker syndrome; PrP; neurodegeneration; misfolding

---

Received April 6, 2006; revised Sept. 22, 2006; accepted Oct. 20, 2006.

Correspondence should be addressed to either of the following: Surachai Supattapone, Department of Biochemistry, Dartmouth Medical School, 7200 Vail Building, Hanover, NH 03755, Email: supattapone{at}Dartmouth.edu; or Patrick J. Dolph, Department of Biology, Dartmouth College, Hanover, NH 03755, Email: partick.j.dolph{at}dartmoth.edu

Related articles in J. Neurosci.:

Mad Fly Disease

Jayanth Chandran and Patrick Lewis
J. Neurosci. 2007 27: 971-972. [Full Text]  

This article has been cited by other articles:

				R. P. Rao, C. Yuan, J. C. Allegood, S. S. Rawat, M. B. Edwards, X. Wang, A. H. Merrill Jr., U. Acharya, and J. K. Acharya Ceramide transfer protein function is essential for normal oxidative stress response and lifespan PNAS, July 3, 2007; 104(27): 11364 - 11369. [Abstract] [Full Text] [PDF]

				J. Chandran and P. Lewis Mad Fly Disease J. Neurosci., January 31, 2007; 27(5): 971 - 972. [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help