Reversal of neuropathology and motor dysfunction in a conditional model of Huntington's disease.

By Ai Yamamoto, J. Lucas, R. Hen. Cell, 2000

1,112 citations recorded by the source corpus.

Neurodegenerative disorders like Huntington's disease (HD) are characterized by progressive and putative irreversible clinical and neuropathological symptoms, including neuronal protein aggregates. Conditional transgenic models of neurodegenerative diseases therefore could be a powerful means to explore the relationship between mutant protein expression and progression of the disease. We have created a conditional model of HD by using the tet-regulatable system. Mice expressing a mutated huntingtin fragment demonstrate neuronal inclusions, characteristic neuropathology, and progressive motor dysfunction. Blockade of expression in symptomatic mice leads to a disappearance of inclusions and an amelioration of the behavioral phenotype. We thus demonstrate that a continuous influx of the mutant protein is required to maintain inclusions and symptoms, raising the possibility that HD may be reversible.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/4eb5ad32ea496745b1a79a3e2e8a696aa917592c

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Citations in the corpus

Sox2 deficiency causes neurodegeneration and impaired neurogenesis in the adult mouse brain (2004, background): “In murine models of Huntington’s and Alzheimer’s disease, parenchymal loss with secondary ventricle enlargement represents the consequence of primary neurodegeneration (Capsoni et al., 2000; Yamamoto et al., 2000; Mantamadiotis et al., 2002).”
Decreased nuclear β‐catenin, tau hyperphosphorylation and neurodegeneration in GSK‐3β conditional transgenic mice (2001, background): “These tTA lines were chosen to allow for restricted, conditional expression in the CNS, with particularly high expression in the forebrain (Mayford et al., 1996; Yamamoto et al., 2000).”
Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. (2003, result): “Our results are consistent tensive astrogliosis and caspase-3 activation, occurs with those from previous studies using the CamKII-tTA with a selective pattern of degeneration that correlates mice to inducibly express other transgenes (Mayford et with p25 expression in Tg mice. al., 1996; Yamamoto e”
Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation. (2001, background): “In strong contrast to these findings, other investigators have demonstrated that formation of protein aggregates correlates with disease progression and the development of neuronal symptoms (Davies et al., 1997; Ona et al., 1999; Yamamoto et al., 2000).”
Role of tau protein in both physiological and pathological conditions. (2004, background): “Animal models of neurodegeneration using the tetracycline-regulated system have the advantage of being able to perform reversible studies (301).”
Sustained therapeutic reversal of Huntington’s disease by transient repression of huntingtin synthesis (2012, positive): “…feasible, transient ASO infusion initiated after symptom onset in an adult animal is consistent with phenotypic reversal in a conditional mouse model (after doxycycline administration to suppress transcription of mutant huntingtin driven by a tet-promoted transgene; Yamamoto et al., 2000).”
What is the role of protein aggregation in neurodegeneration? (2005, background): “If production of mutant huntingtin is stopped, neurons can clear nuclear inclusions effectivel”
Inhibition of PIP4Kγ ameliorates the pathological effects of mutant huntingtin protein (2017, methodology): “The therapeutic potential of this approach is supported by observations in animal and cellular models of HD (Sarkar et al., 2009; King et al., 2008; Singh et al., 2014; Giorgini, 2011; Yamamoto et al., 2000; Lin and Qin, 2013; Sarkar et al., 2007).”
Diseases of Unstable Repeat Expansion: Mechanisms and Common Principles (2005, background): “Coupled with the ability to partially reverse disease phenotypes by halting mutant protein expression, as observed in SCA1 and Huntington disease conditional mouse model”