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The Journal of Neuroscience, May 1, 2002, 22(9):3473-3483

Lentiviral-Mediated Delivery of Mutant Huntingtin in the Striatum of Rats Induces a Selective Neuropathology Modulated by Polyglutamine Repeat Size, Huntingtin Expression Levels, and Protein Length

Luis Pereira de Almeida^{1, 2}, Christopher A. Ross³, Diana Zala^{1, 4}, Patrick Aebischer^{1, 4}, and Nicole Déglon^{1, 4}

¹ Division of Surgical Research and Gene Therapy Center, Lausanne University Medical School, 1011 Lausanne, Switzerland, ² Laboratory of Pharmaceutical Technology, Faculty of Pharmacy and Center for Neuroscience, University of Coimbra, 3000 Coimbra, Portugal, ³ Division of Neurobiology, Departments of Psychiatry and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196, and ⁴ Swiss Federal Institute of Technology Lausanne, 1015 Lausanne, Switzerland

A new strategy based on lentiviral-mediated delivery of mutant huntingtin (htt) was used to create a genetic model of Huntington's disease (HD) in rats and to assess the relative contribution of polyglutamine (CAG) repeat size, htt expression levels, and protein length on the onset and specificity of the pathology. Lentiviral vectors coding for the first 171, 853, and 1520 amino acids of wild-type (19 CAG) or mutant htt (44, 66, and 82 CAG) driven by either the phosphoglycerate kinase 1 (PGK) or the cytomegalovirus (CMV) promoters were injected in rat striatum. A progressive pathology characterized by sequential appearance of ubiquitinated htt aggregates, loss of dopamine- and cAMP-regulated phosphoprotein of 32 kDa staining, and cell death was observed over 6 months with mutant htt. Earlier onset and more severe pathology occurred with shorter fragments, longer CAG repeats, and higher expression levels. Interestingly, the aggregates were predominantly located in the nucleus of PGK-htt171-injected rats, whereas they were present in both the nucleus and processes of CMV-htt171-injected animals expressing lower transgene levels. Finally, a selective sparing of interneurons was observed in animals injected with vectors expressing mutant htt. These data demonstrate that lentiviral-mediated expression of mutant htt provides a robust in vivo genetic model for selective neural degeneration that will facilitate future studies on the pathogenesis of cell death and experimental therapeutics for HD.

Key words: Huntington's disease; genetic model; huntingtin; lentiviral vector; gene delivery; rat

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Copyright © 2002 Society for Neuroscience  0270-6474/02/2293473-11$05.00/0

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