11 results on '"Louisa Dal Cengio"'
Search Results
2. Reducing huntingtin by immunotherapy delays disease progression in a mouse model of Huntington disease
- Author
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Stefan Bartl, Yuanyun Xie, Nalini Potluri, Ratnesh Kesineni, Katlin Hencak, Louisa Dal Cengio, Katja Balazs, Abid Oueslati, Michela Parth, Nina Salhat, Alberto Siddu, Oskar Smrzka, Francesca Cicchetti, Günther Straffler, Michael R. Hayden, and Amber L. Southwell
- Subjects
Huntington disease ,Immunotherapy ,Passive immunization ,Huntingtin lowering therapy ,Extracellular huntingtin ,Transgenic mice ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
In Huntington disease (HD), the mutant huntingtin (mtHTT) protein is the principal cause of pathological changes that initiate primarily along the cortico-striatal axis. mtHTT is ubiquitously expressed and there is, accordingly, growing recognition that HD is a systemic disorder with functional interplay between the brain and the periphery. We have developed a monoclonal antibody, C6–17, targeting an exposed region of HTT near the aa586 Caspase 6 cleavage site. As recently published, mAB C6–17 can block cell-to-cell propagation of mtHTT in vitro. In order to reduce the burden of the mutant protein in vivo, we queried whether extracellular mtHTT could be therapeutically targeted in YAC128 HD mice. In a series of proof of concept experiments, we found that systemic mAB C6–17 treatment resulted in the distribution of the mAB C6–17 to peripheral and CNS tissues and led to the reduction of HTT protein levels. Compared to CTRL mAB or vehicle treated mice, the mAB C6–17 treated YAC128 animals showed improved body weight and motor behaviors, a delayed progression in motor deficits and reduced striatal EM48 immunoreactivity. These results provide the first proof of concept for the feasibility and therapeutic efficacy of an antibody-based anti-HTT passive immunization approach and suggest this modality as a potential new HD treatment strategy.
- Published
- 2024
- Full Text
- View/download PDF
3. DAPK1 Promotes Extrasynaptic GluN2B Phosphorylation and Striatal Spine Instability in the YAC128 Mouse Model of Huntington Disease
- Author
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Mandi E. Schmidt, Nicholas S. Caron, Amirah E. Aly, Fanny L. Lemarié, Louisa Dal Cengio, Yun Ko, Nikola Lazic, Lisa Anderson, Betty Nguyen, Lynn A. Raymond, and Michael R. Hayden
- Subjects
DAPK1 ,synaptic ,GluN2B ,pS1303 ,Huntington disease ,YAC128 ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Huntington disease (HD) is a devastating neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. Disrupted cortico-striatal transmission is an early event that contributes to neuronal spine and synapse dysfunction primarily in striatal medium spiny neurons, the most vulnerable cell type in the disease, but also in neurons of other brain regions including the cortex. Although striatal and cortical neurons eventually degenerate, these synaptic and circuit changes may underlie some of the earliest motor, cognitive, and psychiatric symptoms. Moreover, synaptic dysfunction and spine loss are hypothesized to be therapeutically reversible before neuronal death occurs, and restoration of normal synaptic function may delay neurodegeneration. One of the earliest synaptic alterations to occur in HD mouse models is enhanced striatal extrasynaptic NMDA receptor expression and activity. This activity is mediated primarily through GluN2B subunit-containing receptors and is associated with increased activation of cell death pathways, inhibition of survival signaling, and greater susceptibility to excitotoxicity. Death-associated protein kinase 1 (DAPK1) is a pro-apoptotic kinase highly expressed in neurons during development. In the adult brain, DAPK1 becomes re-activated and recruited to extrasynaptic NMDAR complexes during neuronal death, where it phosphorylates GluN2B at S1303, amplifying toxic receptor function. Approaches to reduce DAPK1 activity have demonstrated benefit in animal models of stroke, Alzheimer’s disease, Parkinson’s disease, and chronic stress, indicating that DAPK1 may be a novel target for neuroprotection. Here, we demonstrate that dysregulation of DAPK1 occurs early in the YAC128 HD mouse model, and contributes to elevated extrasynaptic GluN2B S1303 phosphorylation. Inhibition of DAPK1 normalizes extrasynaptic GluN2B phosphorylation and surface expression, and completely prevents YAC128 striatal spine loss in cortico-striatal co-culture, thus validating DAPK1 as a potential target for synaptic protection in HD and warranting further development of DAPK1-targeted therapies for neurodegeneration.
- Published
- 2020
- Full Text
- View/download PDF
4. Altering cortical input unmasks synaptic phenotypes in the YAC128 cortico-striatal co-culture model of Huntington disease
- Author
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Mandi E. Schmidt, Caodu Buren, James P. Mackay, Daphne Cheung, Louisa Dal Cengio, Lynn A. Raymond, and Michael R. Hayden
- Subjects
Huntington disease ,huntingtin ,synapse ,spine ,dendrite ,corticostriatal co-culture ,Biology (General) ,QH301-705.5 - Abstract
Abstract Background Huntington disease (HD) is a fatal neurodegenerative disorder caused by a CAG expansion in the huntingtin (HTT) gene, leading to selective and progressive neuronal death predominantly in the striatum. Mutant HTT expression causes dysfunctional cortico-striatal (CS) transmission, loss of CS synapses, and striatal medium spiny neuron (MSN) dendritic spine instability prior to neuronal death. Co-culturing cortical and striatal neurons in vitro promotes the formation of functional CS synapses and is a widely used approach to elucidate pathogenic mechanisms of HD and to validate potential synapto-protective therapies. A number of relevant in vivo synaptic phenotypes from the YAC128 HD mouse model, which expresses full-length transgenic human mutant HTT, are recapitulated in CS co-culture by 21 days in vitro (DIV). However, striatal spine loss, which occurs in HD patients and in vivo animal models, has been observed in YAC128 CS co-culture in some studies but not in others, leading to difficulties in reproducing and interpreting results. Here, we investigated whether differences in the relative proportion of cortical and striatal neurons alter YAC128 synaptic phenotypes in this model. Results YAC128 MSNs in 1:1 CS co-culture exhibited impaired dendritic length and complexity compared to wild-type, whereas reducing cortical input using a 1:3 CS ratio revealed a dramatic loss of YAC128 MSN dendritic spines. Chimeric experiments determined that this spine instability was primarily cell autonomous, depending largely on mutant HTT expression in striatal neurons. Moreover, we found that spontaneous electrophysiological MSN activity correlated closely with overall dendritic length, with no differences observed between genotypes in 1:3 co-cultures despite significant YAC128 spine loss. Finally, limiting cortical input with a 1:3 CS ratio impaired the basal survival of YAC128 neurons at DIV21, and this was partially selective for dopamine- and cAMP-regulated phosphoprotein 32-positive MSNs. Conclusions Our findings reconcile previous discordant reports of spine loss in this model, and improve the utility and reliability of the CS co-culture for the development of novel therapeutic strategies for HD.
- Published
- 2018
- Full Text
- View/download PDF
5. BMAL1 loss in oligodendroglial lineage cells dysregulates myelination and sleep
- Author
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Daniela Rojo, Anna Badner, Louisa Dal Cengio, Samuel Kim, Noriaki Sakai, Jacob Greene, Ella Eisinger, Caroline Arellano-Garcia, Lindsey C. Mehl, Mohammad E. Gumma, Rebecca L. Soyk, Julia Ransom, Maya K. Weigel, Belgin Yalçın, Samuel E. Jones, Hanna M. Ollila, Seiji Nishino, and Erin M. Gibson
- Abstract
Myelination depends on maintenance of oligodendrocytes that arise from oligodendrocyte precursor cells (OPCs). We show that the dynamic nature of oligodendroglia and myelination are regulated by the circadian transcription factor BMAL1. Bmal1 knockdown in OPCs during development – but not adulthood – decreases OPC proliferation, whereas BMAL1 regulates OPC morphology throughout life. OPC-specific Bmal1 deficiency impairs remyelination in an age-dependent manner, suggesting that age-associated decrements in circadian regulation of oligodendroglia may contribute to the deficient remyelination potential in demyelinating diseases like multiple sclerosis (MS). This oligodendroglial dysregulation and dysmyelination increase sleep fragmentation in OPC-specific Bmal1 knockout mice, and sleep fragmentation is causally associated with MS. These findings have broad mechanistic and therapeutic implications for numerous brain disorders that include both myelin and sleep phenotypes.One-Sentence SummaryBMAL1 regulates the homeostatic maintenance of oligodendroglia and myelin, that subsequently controls sleep architecture.
- Published
- 2022
6. Potent and sustained huntingtin lowering via AAV5 encoding miRNA preserves striatal volume and cognitive function in a humanized mouse model of Huntington disease
- Author
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Cynthia Brouwers, Pavlina Konstantinova, Amber L. Southwell, Hailey Findlay Black, Michael R. Hayden, Lisa M. Anderson, Nicholas S. Caron, Melvin M. Evers, Xiang Zhu, Seunghyun Ko, Louisa Dal Cengio, Yuanyun Xie, and Sander J. H. van Deventer
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Huntingtin ,RNA Stability ,Genetic Vectors ,Gene Dosage ,Context (language use) ,Biology ,Pharmacology ,Animals, Genetically Modified ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Chemical Biology and Nucleic Acid Chemistry ,Trinucleotide Repeats ,Parvovirinae ,microRNA ,mental disorders ,Genetics ,medicine ,Animals ,Humans ,Molecular Targeted Therapy ,RNA, Messenger ,030304 developmental biology ,Neurons ,0303 health sciences ,Huntingtin Protein ,Base Sequence ,Wild type ,Dependovirus ,medicine.disease ,Corpus Striatum ,3. Good health ,Motor coordination ,Astrogliosis ,nervous system diseases ,Disease Models, Animal ,MicroRNAs ,Huntington Disease ,Tolerability ,nervous system ,Astrocytes ,Humanized mouse ,Neuroglia ,030217 neurology & neurosurgery ,Psychomotor Performance - Abstract
Huntington disease (HD) is a fatal neurodegenerative disease caused by a pathogenic expansion of a CAG repeat in the huntingtin (HTT) gene. There are no disease-modifying therapies for HD. Artificial microRNAs targeting HTT transcripts for degradation have shown preclinical promise and will soon enter human clinical trials. Here, we examine the tolerability and efficacy of non-selective HTT lowering with an AAV5 encoded miRNA targeting human HTT (AAV5-miHTT) in the humanized Hu128/21 mouse model of HD. We show that intrastriatal administration of AAV5-miHTT results in potent and sustained HTT suppression for at least 7 months post-injection. Importantly, non-selective suppression of huntingtin was generally tolerated, however high dose AAV5-miHTT did induce astrogliosis. We observed an improvement of select behavioural and modest neuropathological HD-like phenotypes in Hu128/21 mice, suggesting a potential therapeutic benefit of miRNA-mediated non-selective HTT lowering. Finally, we also observed that potent reduction of wild type HTT (wtHTT) in Hu21 control mice was tolerated up to 7 months post-injection but may induce impairment of motor coordination and striatal atrophy. Taken together, our data suggests that in the context of HD, the therapeutic benefits of mHTT reduction may outweigh the potentially detrimental effects of wtHTT loss following non-selective HTT lowering.
- Published
- 2019
7. DAPK1 Promotes Extrasynaptic GluN2B Phosphorylation and Striatal Spine Instability in the YAC128 Mouse Model of Huntington Disease
- Author
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Michael R. Hayden, Nikola Lazic, Lynn A. Raymond, Nicholas S. Caron, Betty Nguyen, Mandi E. Schmidt, Louisa Dal Cengio, Amirah E. Aly, Lisa M. Anderson, Yun Ko, and Fanny Lemarié
- Subjects
0301 basic medicine ,Programmed cell death ,Excitotoxicity ,Biology ,Medium spiny neuron ,medicine.disease_cause ,YAC128 ,medium spiny neuron ,Neuroprotection ,pS1303 ,lcsh:RC321-571 ,Synapse ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,medicine ,DAPK1 ,Protein kinase A ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Original Research ,Neurodegeneration ,synaptic ,Huntington disease ,NMDA receptor ,medicine.disease ,GluN2B ,030104 developmental biology ,nervous system ,Cellular Neuroscience ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Huntington disease (HD) is a devastating neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. Disrupted cortico-striatal transmission is an early event that contributes to neuronal spine and synapse dysfunction primarily in striatal medium spiny neurons, the most vulnerable cell type in the disease, but also in neurons of other brain regions including the cortex. Although striatal and cortical neurons eventually degenerate, these synaptic and circuit changes may underlie some of the earliest motor, cognitive, and psychiatric symptoms. Moreover, synaptic dysfunction and spine loss are hypothesized to be therapeutically reversible before neuronal death occurs, and restoration of normal synaptic function may delay neurodegeneration. One of the earliest synaptic alterations to occur in HD mouse models is enhanced striatal extrasynaptic NMDA receptor expression and activity. This activity is mediated primarily through GluN2B subunit-containing receptors and is associated with increased activation of cell death pathways, inhibition of survival signaling, and greater susceptibility to excitotoxicity. Death-associated protein kinase 1 (DAPK1) is a pro-apoptotic kinase highly expressed in neurons during development. In the adult brain, DAPK1 becomes re-activated and recruited to extrasynaptic NMDAR complexes during neuronal death, where it phosphorylates GluN2B at S1303, amplifying toxic receptor function. Approaches to reduce DAPK1 activity have demonstrated benefit in animal models of stroke, Alzheimer’s disease, Parkinson’s disease, and chronic stress, indicating that DAPK1 may be a novel target for neuroprotection. Here, we demonstrate that dysregulation of DAPK1 occurs early in the YAC128 HD mouse model, and contributes to elevated extrasynaptic GluN2B S1303 phosphorylation. Inhibition of DAPK1 normalizes extrasynaptic GluN2B phosphorylation and surface expression, and completely prevents YAC128 striatal spine loss in cortico-striatal co-culture, thus validating DAPK1 as a potential target for synaptic protection in HD and warranting further development of DAPK1-targeted therapies for neurodegeneration.
- Published
- 2020
8. Huntingtin suppression restores cognitive function in a mouse model of Huntington’s disease
- Author
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Amber L. Southwell, Hailey Findlay-Black, Yuanyun Xie, Bethany Fitsimmons, Michael E. Østergaard, C. Frank Bennett, Niels H. Skotte, Louisa Dal Cengio, Punit P. Seth, Crystal N. Doty, Michael R. Hayden, Erika B. Villanueva, Douglas R. Langbehn, Lynn A. Raymond, Lisa M. Anderson, Holly B. Kordasiewicz, Eric E. Swayze, Matthew P. Parsons, and Nicholas S. Caron
- Subjects
Male ,Primates ,0301 basic medicine ,Dopamine and cAMP-Regulated Phosphoprotein 32 ,congenital, hereditary, and neonatal diseases and abnormalities ,Huntingtin ,Mutant ,Single-nucleotide polymorphism ,Disease ,Anxiety ,Biology ,medicine.disease_cause ,03 medical and health sciences ,Cognition ,0302 clinical medicine ,Limbic system ,Huntington's disease ,mental disorders ,Limbic System ,medicine ,Animals ,Humans ,Huntingtin Protein ,Mutation ,Behavior, Animal ,Brain ,General Medicine ,Oligonucleotides, Antisense ,medicine.disease ,nervous system diseases ,3. Good health ,Cortex (botany) ,Disease Models, Animal ,Huntington Disease ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,Female ,Mutant Proteins ,Atrophy ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by a mutation in the huntingtin (HTT) protein, resulting in acquisition of toxic functions. Previous studies have shown that lowering mutant HTT has the potential to be broadly beneficial. We previously identified HTT single-nucleotide polymorphisms (SNPs) tightly linked to the HD mutation and developed antisense oligonucleotides (ASOs) targeting HD-SNPs that selectively suppress mutant HTT. We tested allele-specific ASOs in a mouse model of HD. Both early and late treatment reduced cognitive and behavioral impairments in mice. To determine the translational potential of the treatment, we examined the effect of ASO administration on HTT brain expression in nonhuman primates. The treatment induced robust HTT suppression throughout the cortex and limbic system, areas implicated in cognition and psychiatric function. The results suggest that ASOs specifically targeting mutated HTT might have therapeutic effects on HD-mediated cognitive impairments.
- Published
- 2018
9. I09 Antibodies inhibit cell to cell transmission of mutant HTT
- Author
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Alberto Siddu, Abid Oueslati, Halyna Pankevych, Yuanyun Xie, Oskar W. Smrzka, Francesca Cicchetti, Amber L. Southwell, Louisa Dal Cengio, Michael R. Hayden, Michela Parth, Markus Burkert, Seungyun Ko, Nina Salhat, Linda Suzanne David, Erika B. Villanueva, and Stefan Bartl
- Subjects
medicine.anatomical_structure ,biology ,Mutant protein ,Mutant ,Cell ,biology.protein ,medicine ,Huntingtin Protein ,Extracellular ,Antibody ,Mode of action ,Intracellular ,Cell biology - Abstract
The toxic functions of the mutant Huntingtin protein (mutHTT) were studied extensively and in addition to neuronal based symptoms, also peripheral changes upon mutHTT expression were described. An important finding in Huntington’s disease (HD) research from the last years is the discovery of extracellular mutHTT and evidence of cell to cell spreading of the mutant protein. This offers new opportunities for targeting mutHTT by antibodies or target-specific vaccines. Recent publications revealed that mutHTT protein was largely present in a free, non-encapsulated form in the extracellular compartment thereby making it accessible by antibodies. We previously demonstrated peripheral target engagement in actively and passively vaccinated YAC128 mice. In these experiments, mutHTT lowering was accompanied by motor improvement in rotarod assays. We sought to generate an in vitro model for testing the molecular mode of action of newly developed mutHTT targeting antibodies and vaccines. Lead antibody C6–17 was capable of depleting mutHTT and blocking intercellular mutHTT transmission, thereby interfering with a potentially disease amplifying mechanism. Our work sets the ground for the development of new antibody-based therapeutics targeting extracellular HD. It is expected that, besides mutHTT depletion, systemic antibody-based targeting will provide inhibition of mutHTT spreading and intercellular transmission. We understand our systemic approach as an addition to forthcoming tissue-specific mutHTT lowering approaches.
- Published
- 2018
10. Altering cortical input unmasks synaptic phenotypes in the YAC128 cortico-striatal co-culture model of Huntington disease
- Author
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Caodu Buren, James P. Mackay, Mandi E. Schmidt, Louisa Dal Cengio, Michael R. Hayden, Daphne Cheung, and Lynn A. Raymond
- Subjects
0301 basic medicine ,Huntingtin ,Dendritic spine ,huntingtin ,Physiology ,Dendrite ,Mice, Transgenic ,Plant Science ,Striatum ,Biology ,Medium spiny neuron ,spine ,General Biochemistry, Genetics and Molecular Biology ,dendrite ,Synapse ,03 medical and health sciences ,Mice ,0302 clinical medicine ,synapse ,Structural Biology ,Dopamine ,medicine ,Animals ,Humans ,lcsh:QH301-705.5 ,Ecology, Evolution, Behavior and Systematics ,Cerebral Cortex ,Neurons ,Huntingtin Protein ,Reproducibility of Results ,Cell Biology ,Coculture Techniques ,Corpus Striatum ,Electrophysiology ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Huntington Disease ,lcsh:Biology (General) ,nervous system ,Synapses ,Commentary ,General Agricultural and Biological Sciences ,corticostriatal co-culture ,Neuroscience ,030217 neurology & neurosurgery ,Developmental Biology ,Biotechnology ,medicine.drug - Abstract
Background: Huntington disease (HD) is a fatal neurodegenerative disorder caused by a CAG expansion in the huntingtin (HTT) gene, leading to selective and progressive neuronal death predominantly in the striatum. Mutant HTT expression causes dysfunctional cortico-striatal (CS) transmission, loss of CS synapses, and striatal medium spiny neuron (MSN) dendritic spine instability prior to neuronal death. Co-culturing cortical and striatal neurons in vitro promotes the formation of functional CS synapses and is a widely used approach to elucidate pathogenic mechanisms of HD and to validate potential synapto-protective therapies. A number of relevant in vivo synaptic phenotypes from the YAC128 HD mouse model, which expresses full-length transgenic human mutant HTT, are recapitulated in CS co-culture by 21 days in vitro (DIV). However, striatal spine loss, which occurs in HD patients and in vivo animal models, has been observed in YAC128 CS co-culture in some studies but not in others, leading to difficulties in reproducing and interpreting results. Here, we investigated whether differences in the relative proportion of cortical and striatal neurons alter YAC128 synaptic phenotypes in this model. Results: YAC128 MSNs in 1:1 CS co-culture exhibited impaired dendritic length and complexity compared to wild-type, whereas reducing cortical input using a 1:3 CS ratio revealed a dramatic loss of YAC128 MSN dendritic spines. Chimeric experiments determined that this spine instability was primarily cell autonomous, depending largely on mutant HTT expression in striatal neurons. Moreover, we found that spontaneous electrophysiological MSN activity correlated closely with overall dendritic length, with no differences observed between genotypes in 1:3 co-cultures despite significant YAC128 spine loss. Finally, limiting cortical input with a 1:3 CS ratio impaired the basal survival of YAC128 neurons at DIV21, and this was partially selective for dopamine- and cAMP-regulated phosphoprotein 32-positive MSNs. Conclusions: Our findings reconcile previous discordant reports of spine loss in this model, and improve the utility and reliability of the CS co-culture for the development of novel therapeutic strategies for HD.
- Published
- 2018
11. A novel humanized mouse model of Huntington disease for preclinical development of therapeutics targeting mutant huntingtin alleles
- Author
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Crystal N. Doty, Diepiriye G. Iworima, Niels H. Skotte, Daphne Cheung, Mahmoud A. Pouladi, Ramy A. Slama, Xiaofeng Gu, X. William Yang, Jolene Ooi, Hailey Findlay-Black, Louisa Dal Cengio, Erika B. Villanueva, Michael E. Østergaard, Michael R. Hayden, Holly Kordasiewicz, Eric E. Swayze, Sabine Waltl, Chris Kay, Amber L. Southwell, Eugenia Petoukhov, Yuanyun Xie, and Punit P. Seth
- Subjects
0301 basic medicine ,Heterozygote ,congenital, hereditary, and neonatal diseases and abnormalities ,Huntingtin ,Transgene ,Mutant ,Mice, Transgenic ,Biology ,medicine.disease_cause ,Mice ,03 medical and health sciences ,Exon ,0302 clinical medicine ,mental disorders ,Genetics ,medicine ,Animals ,Humans ,Allele ,Molecular Biology ,Alleles ,Genetics (clinical) ,Huntingtin Protein ,Mutation ,Exons ,General Medicine ,Molecular biology ,Phenotype ,Disease Models, Animal ,Huntington Disease ,030104 developmental biology ,Humanized mouse ,030217 neurology & neurosurgery - Abstract
Huntington disease (HD) is a neurodegenerative disease caused by a mutation in the huntingtin (HTT) gene. HTT is a large protein, interacts with many partners and is involved in many cellular pathways, which are perturbed in HD. Therapies targeting HTT directly are likely to provide the most global benefit. Thus there is a need for preclinical models of HD recapitulating human HTT genetics. We previously generated a humanized mouse model of HD, Hu97/18, by intercrossing BACHD and YAC18 mice with knockout of the endogenous mouse HD homolog (Hdh). Hu97/18 mice recapitulate the genetics of HD, having two full-length, genomic human HTT transgenes heterozygous for the HD mutation and polymorphisms associated with HD in populations of Caucasian descent. We have now generated a companion model, Hu128/21, by intercrossing YAC128 and BAC21 mice on the Hdh-/- background. Hu128/21 mice have two full-length, genomic human HTT transgenes heterozygous for the HD mutation and polymorphisms associated with HD in populations of East Asian descent and in a minority of patients from other ethnic groups. Hu128/21 mice display a wide variety of HD-like phenotypes that are similar to YAC128 mice. Additionally, both transgenes in Hu128/21 mice match the human HTT exon 1 reference sequence. Conversely, the BACHD transgene carries a floxed, synthetic exon 1 sequence. Hu128/21 mice will be useful for investigations of human HTT that cannot be addressed in Hu97/18 mice, for developing therapies targeted to exon 1, and for preclinical screening of personalized HTT lowering therapies in HD patients of East Asian descent.
- Published
- 2017
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