Lentiviral-Mediated Delivery of Mutant Huntingtin in the Striatum of Rats Induces a Selective Neuropathology Modulated by Polyglutamine Repeat Size, Huntingtin Expression Levels, and Protein Length

Almeida, Luís Pereira de; Ross, Christopher A.; Zala, Diana; Aebischer, Patrick; Déglon, Nicole

doi:10.1523/jneurosci.22-09-03473.2002

Cited by 190 publications

(155 citation statements)

References 70 publications

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“…Lentivirus has been used to generate a rat model of HD (36). Delivery of truncated mutant Htt in lentivirus produced neuropathological features of HD but not behavioral phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits

DiFiglia

Sena‐Esteves

Chase³

et al. 2007

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

372

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Huntington's disease (HD) is a neurodegenerative disorder caused by expansion of a CAG repeat in the huntingtin (Htt) gene. HD is autosomal dominant and, in theory, amenable to therapeutic RNA silencing. We introduced cholesterol-conjugated small interfering RNA duplexes (cc-siRNA) targeting human Htt mRNA (siRNA-Htt) into mouse striata that also received adeno-associated virus containing either expanded (100 CAG) or wild-type (18 CAG) Htt cDNA encoding huntingtin (Htt) 1-400. Adeno-associated virus delivery to striatum and overlying cortex of the mutant Htt gene, but not the wild type, produced neuropathology and motor deficits. Treatment with cc-siRNA-Htt in mice with mutant Htt prolonged survival of striatal neurons, reduced neuropil aggregates, diminished inclusion size, and lowered the frequency of clasping and footslips on balance beam. cc-siRNA-Htt was designed to target human wild-type and mutant Htt and decreased levels of both in the striatum. Our findings indicate that a single administration into the adult striatum of an siRNA targeting Htt can silence mutant Htt, attenuate neuronal pathology, and delay the abnormal behavioral phenotype observed in a rapid-onset, viral transgenic mouse model of HD.

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“…Lentivirus has been used to generate a rat model of HD (36). Delivery of truncated mutant Htt in lentivirus produced neuropathological features of HD but not behavioral phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits

DiFiglia

Sena‐Esteves

Chase³

et al. 2007

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

372

301

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“…A caveat, however, is that it is unknown whether these isolated neurons have already been compromised in vivo. 3) In vivo, viral-mediated expression of polyQ-htt exclusively in the striatum results in reversible formation of inclusions, transcriptional dysregulation, and MSN death, while sparing interneurons [24,38,39]. Conversely, a decrease in striatal polyQ-htt expression mediated by viral siRNA largely corrects many of these deficits both in viral and transgenic HD models [40,41].…”

Section: Evidence Supporting Intrinsic Vulnerability Of Msns In Hdmentioning

confidence: 99%

Huntington's Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Disease

Ehrlich

2012

Neurotherapeutics

114

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Huntington's disease is an autosomal dominant disorder caused by a mutation in the gene encoding the protein huntingtin on chromosome 4. The mutation is an expanded CAG repeat in the first exon, encoding a polyglutamine tract. If the polyglutamine tract is >40, penetrance is 100% and death is inevitable. Despite the widespread expression of huntingtin, HD has long been considered primarily as a disease of the striatum. It is characterized by selective vulnerability with dysfunction followed by death of the medium size spiny neuron. Considerable effort is being expended to determine whether striatal damage is cell-autonomous, non-cell-autonomous, requiring cell-cell and region to region communication, or both. We review data supporting both mechanisms. We also attempt to organize the data into common mechanisms that may arise outside the medium, spiny neuron, but ultimately have their greatest impact in the striatum. characterized by selective, or perhaps better described as differential [2], vulnerability with degeneration and death of the medium spiny neuron (MSN). The Gamma-aminobutyric acid (GABA)ergic MSN represents 95% of striatal neurons. They are all output neurons, with extensive intra-striatal connections with other MSNs and striatal interneurons. For the last two decades, increased attention has been paid to the pathology in the cortex (particularly in layers V and VI [3]), which contains the corticostriatal projection neurons.Prior to identification of the HTT gene, the huntingtin protein, and the nature of its mutation, it was assumed that selective neuronal vulnerability in HD would be conferred by the expression pattern of the mutated protein (polyQ-htt). As it is now apparent, htt is expressed throughout the nervous system and periphery, without a preference for, or higher level in, MSNs or cortical projection neurons [4].In the absence of enriched expression of a mutated protein, neuronal subtype vulnerability was assumed to arise from unique protein interactions. For example, in the study of another polyQ disease, spinocerebellar ataxia 7, the interaction between ataxin-7 and the homeobox protein CRX in the retina was reported to specifically lead to pathology [5]. In a followup study, the specific role of CRX was not confirmed [6]. To complicate matters further, the same group recently demonstrated that the interactions between a mutant polyQ protein, Ataxin-1, and 14-3-3epsilon differentially affects disease state in cerebellum and brainstem, both of which are vulnerable regions [7]. The regional distribution of the described huntingtin interacting proteins by and large does not explain MSN vulnerability [8][9][10]. One exception is the htt interacting protein RASD2/Rhes (Ras homologue enriched in striatum), which is striatal-specific. It is a small G-protein that mediates sumoylation of polyQ-htt, and thereby its neurotoxicity.

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“…A similar approach has been reported in animal models of Parkinson's disease, using HSV vector-mediated Alzheimer's gene therapy C-S Hong et al LV 35 or AAV, 36 to overexpress a-synuclein, and Huntington's disease, using AAV-mediated expression of expanded polyglutamine tracts 37 or LV-mediated expression of Huntingtin. 38 Aside from its intrinsic flexibility and convenience, 39 the major attraction of this type of model system is that the vector can be delivered to species that are not amenable to transgenic manipulation, such as rats and monkeys, but which have special relevance to the study of human brain function and pathology. The main advantage of using the LV system from the standpoint of the present studies is that the rapid elevation in tissue Ab levels produced by vector transduction allows us to test different vectors for their desired effects in targeting Ab expression over a short time course in vivo, without the need to breed special transgenic lines of rodents.…”

Section: An In Vivo Model Of Amyloid-b Peptide Overproductionmentioning

confidence: 99%

Herpes simplex virus RNAi and neprilysin gene transfer vectors reduce accumulation of Alzheimer's disease-related amyloid-β peptide in vivo

et al. 2006

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Lentiviral-Mediated Delivery of Mutant Huntingtin in the Striatum of Rats Induces a Selective Neuropathology Modulated by Polyglutamine Repeat Size, Huntingtin Expression Levels, and Protein Length

Cited by 190 publications

References 70 publications

Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits

Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits

Huntington's Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Disease

Herpes simplex virus RNAi and neprilysin gene transfer vectors reduce accumulation of Alzheimer's disease-related amyloid-β peptide in vivo

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