Neuronal intranuclear inclusions and neuropil aggregates in HdhCAG(150) knockin mice

Tallaksen-Greene, Sara J.; Crouse, Andrew B.; Hunter, Jesse M.; Detloff, Peter J.; Albin, Roger L.

doi:10.1016/j.neuroscience.2004.10.037

Cited by 57 publications

(33 citation statements)

References 69 publications

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“…Hdh (CAG)150 mice have no overt changes in other brain regions, as shown by GABA A /benzodiazepine binding. These results are consistent with our previous description of almost uniquely high expression of striatal NIIs in this line (Tallaksen-Greene et al, 2005).…”

Section: Discussionsupporting

confidence: 94%

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Longitudinal Evaluation of theHdh^(CAG)150Knock-In Murine Model of Huntington's Disease

Heng¹,

Tallaksen-Greene²,

Detloff³

et al. 2007

J. Neurosci.

141

134

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Section: Discussionsupporting

confidence: 94%

“…Time points are selected based on previously published neuronal intranuclear inclusion (NII) data (Tallaksen-Greene et al, 2005). In that study, diffuse nuclear htt immunoreactivity was apparent within MSNs ϳ20 weeks of age, and some htt-immunoreactive NIIs were apparent by 40 weeks.…”

Section: Behavioral Examinationmentioning

confidence: 99%

Longitudinal Evaluation of theHdh^(CAG)150Knock-In Murine Model of Huntington's Disease

Heng¹,

Tallaksen-Greene²,

Detloff³

et al. 2007

J. Neurosci.

141

134

View full text Add to dashboard Cite

“…A similar association of behavioral abnormality and neuropathology with the development of neuropil or neuritic aggregates has been noted in other mutant mouse models of HD as well (Schilling et al, 1999;Li et al, 2000;Laforet et al, 2001;Lin et al, 2001;Menalled et al, 2002). The neuropil aggregates are localized to dendrites, axons, and perhaps axon terminals (Tallaksen-Greene et al, 2005). Given the disruptions in subcellular structure they are likely to cause, neuropil aggregates may interfere with dendritic and axonal traf-…”

supporting

confidence: 63%

R6/2 neurons with intranuclear inclusions survive for prolonged periods in the brains of chimeric mice

Reiner

Mar

Deng

et al. 2007

J of Comparative Neurology

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The R6/2 mouse possesses mutant exon 1 of human Hdh, and R6/2 mice with 150 CAG repeats show neurological abnormalities by 10 weeks and die by 15 weeks. Few brain abnormalities, however, are evident at death, other than widespread ubiquitinated neuronal intranuclear inclusions (NIIs). We constructed R6/2t+/t- <--> wildtype (WT) chimeric mice to prolong survival of R6/2 cells and determine if neuronal death and/or neuronal injury become evident with longer survival. ROSA26 mice (which bear a lacZ transgene) were used as WT to distinguish between R6/2 and WT neurons. Chimeric mice consisting partly of R6/2 cells lived longer than pure R6/2 mice (up to 10 months), with the survival proportional to the R6/2 contribution. Genotypically R6/2 cells formed NIIs in the chimeras, and these NIIs grew only slightly larger than in 12-week pure R6/2 mice, even after 10 months. Additionally, neuropil aggregates formed near R6/2 neurons in chimeric mice older than 15 weeks. Thus, R6/2 neurons could survive well beyond 15 weeks in chimeras. Moreover, little neuronal degeneration was evident in either cortex or striatum by routine histological stains. Nonetheless, striatal shrinkage and ventricular enlargement occurred, and striatal projection neuron markers characteristically reduced in Huntington's disease were diminished. Consistent with such abnormalities, cortex and striatum in chimeras showed increased astrocytic glial fibrillary acidic protein. These results suggest that while cortical and striatal neurons can survive nearly a year with nuclear and extranuclear aggregates of mutant huntingtin, such lengthy survival does reveal cortical and striatal abnormality brought on by the truncated mutant protein.

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“…On the other hand, calbindin is decreased in PCs but not in the striatum [25]. 2) In several HD mouse models with ubiquitous transgene expression, inclusion formation and/or cell loss is preponderant in the striatum, and sometimes even MSN-subtype specific [31][32][33]. These data confirm that HD mouse models replicate the human pattern of neuronal disease.…”

Section: Evidence Supporting Intrinsic Vulnerability Of Msns In Hdmentioning

confidence: 60%

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

Ehrlich

2012

Neurotherapeutics

126

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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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Neuronal intranuclear inclusions and neuropil aggregates in HdhCAG(150) knockin mice

Cited by 57 publications

References 69 publications

Longitudinal Evaluation of theHdh^(CAG)150Knock-In Murine Model of Huntington's Disease

Longitudinal Evaluation of theHdh^(CAG)150Knock-In Murine Model of Huntington's Disease

R6/2 neurons with intranuclear inclusions survive for prolonged periods in the brains of chimeric mice

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

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Neuronal intranuclear inclusions and neuropil aggregates in HdhCAG(150) knockin mice

Cited by 57 publications

References 69 publications

Longitudinal Evaluation of theHdh(CAG)150Knock-In Murine Model of Huntington's Disease

Longitudinal Evaluation of theHdh(CAG)150Knock-In Murine Model of Huntington's Disease

R6/2 neurons with intranuclear inclusions survive for prolonged periods in the brains of chimeric mice

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

Contact Info

Product

Resources

About

Longitudinal Evaluation of theHdh^(CAG)150Knock-In Murine Model of Huntington's Disease

Longitudinal Evaluation of theHdh^(CAG)150Knock-In Murine Model of Huntington's Disease