Genetic mouse models of Huntington's and Parkinson's diseases: Illuminating but imperfect

Mental Retardation Research Center, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Trends in Neurosciences (Impact Factor: 13.56). 12/2004; 27(11):691-7. DOI: 10.1016/j.tins.2004.08.008
Source: PubMed


Genetic mouse models based on identification of genes that cause Huntington's and Parkinson's diseases have revolutionized understanding of the mechanistic pathophysiological progression of these disorders. These models allow the earliest manifestations of the diseases to be identified, and they display behavioral, neuropathological and electrophysiological deficits that can be followed over time in mechanistic and drug studies. An intriguing feature is that they do not reproduce the relatively selective and massive cell loss characterizing the human diseases. There is more information on Huntington's disease models because the disorder involves a single gene that was identified over ten years ago; genetic mutations causing Parkinson's disease are rare and were discovered more recently, and models of the disease have been generated only within the past few years.

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    • "Accordingly, an early decrease of cholesterol production in the HD brain might be detrimental for neuronal activities. Abnormalities in synaptic communication within the striatum and between the cortex and striatum occur long before, or in the absence of, cell death in HD animal models (Milnerwood & Raymond, 2010) and cognitive disturbances have been observed decades before predicted clinical diagnosis in HD gene carriers (Levine et al, 2004; Paulsen & Long, 2014). Similarly, brain cholesterol biosynthesis is significantly reduced before the onset of motor symptoms in all the HD animal models analyzed so far (Valenza et al, 2007a,b) and synaptosomes —a compartment dedicated to impulse transmission and neurotransmitter release—carry suboptimal levels of sterols in the early stages of HD in one mouse model (Valenza et al, 2010). "
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    ABSTRACT: Brain cholesterol biosynthesis and cholesterol levels are reduced in mouse models of Huntington's disease (HD), suggesting that locally synthesized, newly formed cholesterol is less available to neurons. This may be detrimental for neuronal function, especially given that locally synthesized cholesterol is implicated in synapse integrity and remodeling. Here, we used biodegradable and biocompatible polymeric nanoparticles (NPs) modified with glycopeptides (g7) and loaded with cholesterol (g7-NPs-Chol), which per se is not blood-brain barrier (BBB) permeable, to obtain high-rate cholesterol delivery into the brain after intraperitoneal injection in HD mice. We report that g7-NPs, in contrast to unmodified NPs, efficiently crossed the BBB and localized in glial and neuronal cells in different brain regions. We also found that repeated systemic delivery of g7-NPs-Chol rescued synaptic and cognitive dysfunction and partially improved global activity in HD mice. These results demonstrate that cholesterol supplementation to the HD brain reverses functional alterations associated with HD and highlight the potential of this new drug-administration route to the diseased brain.
    Preview · Article · Nov 2015 · EMBO Molecular Medicine
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    • "Alterations in striatal PKA function have been shown to impair motor execution and motor learning (Brandon et al., 1998; Chagniel et al., 2014; Kheirbek et al., 2009). In HD, severe neuronal dysfunction precedes degeneration and is probably the major cause of many motor symptoms (Levine et al., 2004). Therefore, we hypothesized that normalization of PKA activity in the striatum could also benefit motor abnormalities . "
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    ABSTRACT: Stimulation of dopamine D1 receptor (D1R) and adenosine A2A receptor (A2AR) increases cAMP-dependent protein kinase (PKA) activity in the brain. In Huntington's disease, by essentially unknown mechanisms, PKA activity is increased in the hippocampus of mouse models and patients and contributes to hippocampal-dependent cognitive impairment in R6 mice. Here, we show for the first time that D1R and A2AR density and functional efficiency are increased in hippocampal nerve terminals from R6/1 mice, which accounts for increased cAMP levels and PKA signaling. In contrast, PKA signaling was not altered in the hippocampus of Hdh(Q7/Q111) mice, a full-length HD model. In line with these findings, chronic (but not acute) combined treatment with D1R plus A2AR antagonists (SCH23390 and SCH58261, respectively) normalizes PKA activity in the hippocampus, facilitates long-term potentiation in behaving R6/1 mice, and ameliorates cognitive dysfunction. By contrast, chronic treatment with either D1R or A2AR antagonist alone does not modify PKA activity or improve cognitive dysfunction in R6/1 mice. Hyperactivation of both D1R and A2AR occurs in HD striatum and chronic treatment with D1R plus A2AR antagonists normalizes striatal PKA activity but it does not affect motor dysfunction in R6/1 mice. In conclusion, we show that parallel alterations in dopaminergic and adenosinergic signaling in the hippocampus contribute to increase PKA activity, which in turn selectively participates in hippocampal-dependent learning and memory deficits in HD. In addition, our results point to the chronic inhibition of both D1R and A2AR as a novel therapeutic strategy to manage early cognitive impairment in this neurodegenerative disease. Copyright © 2014. Published by Elsevier Inc.
    Full-text · Article · Nov 2014 · Neurobiology of Disease
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    • "To study the underlying mechanisms of sleep-wake disturbances associated with HD, we first need to identify suitable animal models that recapitulate as many symptom sets of HD as possible. While there are numerous mouse models of HD, no single model has yet been determined to be the ideal mirror of human HD [17]. Two examples of transgenic insertion HD mouse models are the exon 1-fragment model (R6/2 [18]) and the stable 90Q-repeat with full-length human HTT gene model (BACHD [19]). "
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    ABSTRACT: Sleep and circadian disruptions are commonly reported by patients with neurodegenerative diseases, suggesting these may be an endophenotype of the disorders. Several mouse models of Huntington's disease (HD) that recapitulate the disease progression and motor dysfunction of HD also exhibit sleep and circadian rhythm disruption. Of these, the strongest effects are observed in the transgenic models with multiple copies of mutant huntingtin gene. For developing treatments of the human disease, knock-in (KI) models offer advantages of genetic precision of the insertion and control of mutation copy number. Therefore, we assayed locomotor activity and immobility-defined sleep in a new model of HD with an expansion of the KI repeats (Q175). We found evidence for gene dose- and age-dependent circadian disruption in the behavior of the Q175 line. We did not see evidence for loss of cells or disruption of the molecular oscillator in the master pacemaker, the suprachiasmatic nucleus (SCN). The combination of the precise genetic targeting in the Q175 model and the observed sleep and circadian disruptions make it tractable to study the interaction of the underlying pathology of HD and the mechanisms by which the disruptions occur.
    Full-text · Article · Jul 2013 · PLoS ONE
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