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The Journal of Neuroscience, October 19, 2005, 25(42):9773-9781; doi:10.1523/JNEUROSCI.3183-05.2005

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Neurobiology of Disease
Full Motor Recovery Despite Striatal Neuron Loss and Formation of Irreversible Amyloid-Like Inclusions in a Conditional Mouse Model of Huntington's Disease

Miguel Díaz-Hernández,¹ Jesús Torres-Peraza,² Alejandro Salvatori-Abarca,¹ María A. Morán,³ Pilar Gómez-Ramos,³ Jordi Alberch,² and José J. Lucas¹

¹Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Científicas/Universidad Autónoma de Madrid, 28049 Madrid, Spain, ²Departamento de Biología Celular i Anatomía Patológica, Facultat de Medicina, L'Institut d'Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, E-08036 Barcelona, Spain, and ³Departamento de Morfología, Facultad de Medicina, Universidad Autónoma de Madrid, 28029 Madrid, Spain

The primary mechanism responsible for Huntington's disease remains unknown. Postulated early pathogenic events include the following: impaired protein folding, altered protein degradation, mitochondrial dysfunction, and transcriptional dysregulation. Although related therapies can delay disease progression in mouse models, they target downstream and probably indirect effects of mutant-huntingtin expression. Accordingly, in case they prove beneficial in humans, they might only palliate some aspects of disease. Our previous studies in the Tet/HD94 conditional model and the recently reported efficacy of RNA interference against mutant huntingtin in another mouse model support silencing mutant-huntingtin expression as a valid therapeutic approach that has the advantage of targeting toxicity at its root. Here, we address whether gene silencing can still be beneficial in the late stages of disease with detectable striatal neuron loss. Stereological analysis was applied to determine an age at which Tet/HD94 mice show a decrease in the number of striatal neurons. Then, progression of neuropathology and motor phenotype were analyzed in mice that were allowed to continue expressing mutant huntingtin and in mice that no longer expressed it. Neuronal loss did not revert in gene-off mice, but the additional loss that takes place in gene-on mice was prevented. The total number of huntingtin-containing inclusions dramatically reverted, but a small fraction of inclusions positive for the amyloid dye thioflavin-S remained. Interestingly, despite a 20% decrease in striatal neurons and the presence of amyloid-like irreversible inclusions, gene-off mice fully recover from their motor deficit, thus ruling out amyloid-like huntingtin inclusions as the main toxic species and suggesting that gene-silencing therapies might work in late stages of disease.

Key words: Huntington's disease; reversal; conditional mouse model; amyloid-like inclusions; stereology; neuronal loss

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Received June 3, 2005; revised September 2, 2005; accepted September 3, 2005.

This article has been cited by other articles:

				M. Diaz-Hernandez, M. Diez-Zaera, J. Sanchez-Nogueiro, R. Gomez-Villafuertes, J. M. Canals, J. Alberch, M. T. Miras-Portugal, and J. J. Lucas Altered P2X7-receptor level and function in mouse models of Huntington's disease and therapeutic efficacy of antagonist administration FASEB J, June 1, 2009; 23(6): 1893 - 1906. [Abstract] [Full Text] [PDF]

				H. Seo, W. Kim, and O. Isacson Compensatory changes in the ubiquitin-proteasome system, brain-derived neurotrophic factor and mitochondrial complex II/III in YAC72 and R6/2 transgenic mice partially model Huntington's disease patients Hum. Mol. Genet., October 15, 2008; 17(20): 3144 - 3153. [Abstract] [Full Text] [PDF]

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