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

Levine, Michael S.; Cepeda, Carlos; Hickey, Miriam A.; Fleming, Sheila M.; Chesselet, Marie‐Françoise

doi:10.1016/j.tins.2004.08.008

Cited by 170 publications

(140 citation statements)

References 68 publications

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“…Stereological analysis provides clear evidence that cell death occurred, whereas Drd1a and Drd2 in situ hybridization data confirm that cell death is indeed restricted to the Drd1aϩ cell compartment. Detailed behavioral analyses of MUT mice revealed a phenotype, elements of which are observed in other models of HD (15,16,23). We demonstrate that primary loss of a Drd1aϩ subpopulation can produce a tail suspension-induced hindlimb dystonic phenotype, locomotor hyperactivity, and significant changes in oral behavioral topographies.…”

Section: Discussionmentioning

confidence: 57%

“…Death of striatal projection neurons may have secondary effects on corticostriatal neurons if these cortical neurons depended on striatal-derived trophic factors. Changes in cortical pyramidal neurons have been identified in other HD transgenic models (16), and it is not clear whether these changes are related to the primary disease process within the cortex or secondary to striatal pathology.…”

Section: Discussionmentioning

confidence: 99%

“…What are secondary consequences, particularly on corticostriatal projection neurons, of the death of a specific population of cells within the striatum? HD animal models generated to date either use neurotoxic striatal lesioning (14) or express a CAG repeat expanded Huntingtin gene (15,16). These approaches ultimately result in the death of cells in both Drd1aϩ and Drd2ϩ striatal compartments.…”

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confidence: 99%

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Ablation of D1 dopamine receptor-expressing cells generates mice with seizures, dystonia, hyperactivity, and impaired oral behavior

Gantois

Fang

Jiang

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Huntington's disease is characterized by death of striatal projection neurons. We used a Cre/Lox transgenic approach to generate an animal model in which D1 dopamine receptor (Drd1a)؉ cells are progressively ablated in the postnatal brain. Striatal Drd1a, substance P, and dynorphin expression is progressively lost, whereas D2 dopamine receptor (Drd2) and enkephalin expression is up-regulated. Magnetic resonance spectroscopic analysis demonstrated early elevation of the striatal choline/creatine ratio, a finding associated with extensive reactive striatal astrogliosis. Sequential MRI demonstrated a progressive reduction in striatal volume and secondary ventricular enlargement confirmed to be due to loss of striatal cells. Mutant mice had normal gait and rotarod performance but displayed hindlimb dystonia, locomotor hyperactivity, and handling-induced electrographically verified spontaneous seizures. Ethological assessment identified an increase in rearing and impairments in the oral behaviors of sifting and chewing. In line with the limbic seizure profile, cell loss, astrogliosis, microgliosis, and down-regulated dynorphin expression were seen in the hippocampal dentate gyrus. This study specifically implicates Drd1a؉ cell loss with tail suspension hindlimb dystonia, hyperactivity, and abnormal oral function. The latter may relate to the speech and swallowing disturbances and the classic sign of tongueprotrusion motor impersistence observed in Huntington's disease. In addition, the findings of this study support the notion that Drd1a and Drd2 are segregated on striatal projection neurons. striatum ͉ Cre ͉ Huntington's disease T he nigrostriatal pathway projects from the midbrain substantia nigra pars compacta to innervate the dorsal striatum. Dopamine is released from dopaminergic terminals in the striatum to regulate motor activity and eating behavior (1). Early studies suggested that dopamine D1 (Drd1a) and D2 receptors (Drd2) are segregated on striatal projection neurons; the Drd1a is expressed on substance P and dynorphin-positive striatal neurons, which project directly to the substantia nigra pars reticulata/entopeduncular complex (known as the direct pathway), whereas Drd2 is preferentially expressed on enkephalin-positive striatopallidal projecting neurons (2). Neurons within the globus pallidus then project to the subthalamic nucleus, which in turn relays to the substantia nigra pars reticulata/entopeduncular complex (known as the indirect pathway). Dopamine also modulates the activity of glutamatergic corticostriatal input on striatal projection neurons.Idiopathic Parkinson's disease is characterized by the death of dopaminergic neurons; however, rare Parkinsonian syndromes have been identified in which the defect is associated with cell death in the dopamine-responsive neurons in the striatum (3-6). Huntington's disease (HD) (7-10), a neurodegenerative condition with motor, cognitive, and psychiatric disturbances, also involves death of dopamine receptor-expressing striatal projection neurons. Several ...

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Ablation of D1 dopamine receptor-expressing cells generates mice with seizures, dystonia, hyperactivity, and impaired oral behavior

Gantois

Fang

Jiang

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…It is known that the intermediates of cholesterol biosynthesis are critical for neurite outgrowth, synaptic activity and stability. Neurite loss is an early manifestation of various neurodegenerative disorders, including HD, in which morphological abnormalities of the brain and defects in synaptic activity have been documented (Li et al, 2003;Levine et al, 2004;Schulz et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Dysfunction of the Cholesterol Biosynthetic Pathway in Huntington's Disease

Valenza¹,

Rigamonti²,

Goffredo³

et al. 2005

J. Neurosci.

243

206

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The expansion of a polyglutamine tract in the ubiquitously expressed huntingtin protein causes Huntington's disease (HD), a dominantly inherited neurodegenerative disease. We show that the activity of the cholesterol biosynthetic pathway is altered in HD. In particular, the transcription of key genes of the cholesterol biosynthetic pathway is severely affected in vivo in brain tissue from HD mice and in human postmortem striatal and cortical tissue; this molecular dysfunction is biologically relevant because cholesterol biosynthesis is reduced in cultured human HD cells, and total cholesterol mass is significantly decreased in the CNS of HD mice and in brain-derived ST14A cells in which the expression of mutant huntingtin has been turned on. The transcription of the genes of the cholesterol biosynthetic pathway is regulated via the activity of sterol regulatory element-binding proteins (SREBPs), and we found an ϳ50% reduction in the amount of the active nuclear form of SREBP in HD cells and mouse brain tissue. As a consequence, mutant huntingtin reduces the transactivation of an SRE-luciferase construct even under conditions of SREBP overexpression or in the presence of an exogenous N-terminal active form of SREBP. Finally, the addition of exogenous cholesterol to striatal neurons expressing mutant huntingtin prevents their death in a dosedependent manner. We conclude that the cholesterol biosynthetic pathway is impaired in HD cells, mice, and human subjects, and that the search for HD therapies should also consider cholesterol levels as both a potential target and disease biomarker.

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“…Screening of putative therapies for HD has benefited from the existence of several HD mouse models (11,12). HD-like phenotypes are displayed in knock-in mice (13,14), drug-induced models (15), and transgenic mice expressing full-length mutant htt (e.g., yeast artificial chromosome-transgenic mice) (16)(17)(18) or an N-terminal fragment of htt (10,19,20).…”

mentioning

confidence: 99%

RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model

Harper

Staber

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

624

474

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Huntington's disease (HD) is a fatal, dominant neurogenetic disorder. HD results from polyglutamine repeat expansion (CAG codon, Q) in exon 1 of HD, conferring a toxic gain of function on the protein huntingtin (htt). Currently, no preventative treatment exists for HD. RNA interference (RNAi) has emerged as a potential therapeutic tool for treating dominant diseases by directly reducing disease gene expression. Here, we show that RNAi directed against mutant human htt reduced htt mRNA and protein expression in cell culture and in HD mouse brain. Importantly, htt gene silencing improved behavioral and neuropathological abnormalities associated with HD. Our data provide support for the further development of RNAi for HD therapy.short hairpin RNAs ͉ triplet repeat diseases ͉ gene therapy ͉ nanomedicine

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

Cited by 170 publications

References 68 publications

Ablation of D1 dopamine receptor-expressing cells generates mice with seizures, dystonia, hyperactivity, and impaired oral behavior

Ablation of D1 dopamine receptor-expressing cells generates mice with seizures, dystonia, hyperactivity, and impaired oral behavior

Dysfunction of the Cholesterol Biosynthetic Pathway in Huntington's Disease

RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model

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