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The Journal of Neuroscience, February 4, 2009, 29(5):1343-1349; doi:10.1523/JNEUROSCI.6039-08.2009

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Neurobiology of Disease
Decreased BDNF Levels Are a Major Contributor to the Embryonic Phenotype of Huntingtin Knockdown Zebrafish

Heike Diekmann,^1,3 Oleg Anichtchik,¹ Angeleen Fleming,¹ Marie Futter,² Paul Goldsmith,¹ Alan Roach,^1,3 and David C. Rubinsztein²

¹Summit (Cambridge) Ltd., Cambridge CB25 9TN, United Kingdom, ²Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 2XY, United Kingdom, and ³Summit plc, Abingdon OX14 4RY, United Kingdom

Correspondence should be addressed to David C. Rubinsztein, Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK. Email: dcr1000{at}hermes.cam.ac.uk

Huntington's disease (HD) is an autosomal dominant, neurodegenerative condition caused by a CAG trinucleotide repeat expansion that is translated into an abnormally long polyglutamine tract in the protein huntingtin. Genetic and transgenic studies suggest that the mutation causes disease predominantly via gain-of-function mechanisms. However, loss of normal huntingtin function resulting from the polyglutamine expansion might also contribute to the pathogenesis of HD. Here, we have studied the effects of huntingtin knockdown in zebrafish using morpholino antisense oligonucleotides, as its huntingtin orthologue has 70% amino acid identity with the human protein. Reduced huntingtin levels did not impact on gastrulation and early development, but caused massive apoptosis of neuronal cells by 24 hpf. This was accompanied by impaired neuronal development, resulting in small eyes and heads and enlargement of brain ventricles. Older huntingtin knockdown fish developed lower jaw abnormalities with most branchial arches missing. Molecular analysis revealed that BDNF expression was reduced by 50%. Reduction of BDNF levels by injection of a BDNF morpholino resulted in phenotypes very similar to those seen in huntingtin knockdown zebrafish. The phenotypes of both huntingtin- and BDNF-knockdown zebrafish showed significant rescue when treated with exogenous BDNF protein. This underscores the physiological importance of huntingtin as a regulator of BDNF production and suggests that loss of BDNF is a major cause of the developmental abnormalities seen with huntingtin knockdown in zebrafish. Increasing BDNF expression may represent a useful strategy for Huntington's disease treatment.

Key words: huntingtin; BDNF; zebrafish; knockdown; animal model; neurotrophic factor

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Received Sept. 12, 2008; revised Dec. 19, 2008; accepted Dec. 21, 2008.

Correspondence should be addressed to David C. Rubinsztein, Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK. Email: dcr1000{at}hermes.cam.ac.uk

This article has been cited by other articles:

				T. L. Henshall, B. Tucker, A. L. Lumsden, S. Nornes, M. T. Lardelli, and R. I. Richards Selective neuronal requirement for huntingtin in the developing zebrafish Hum. Mol. Genet., December 15, 2009; 18(24): 4830 - 4842. [Abstract] [Full Text] [PDF]

				M Futter, H Diekmann, E Schoenmakers, O Sadiq, K Chatterjee, and D C Rubinsztein Wild-type but not mutant huntingtin modulates the transcriptional activity of liver X receptors J. Med. Genet., July 1, 2009; 46(7): 438 - 446. [Abstract] [Full Text] [PDF]

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