Morphometric Demonstration of Atrophic Changes in the Cerebral Cortex, White Matter, and Neostriatum in Huntington's Disease

Monte, Suzanne M. de la; Vonsattel, Jean‐Paul; Richardson, Edward P.

doi:10.1097/00005072-198809000-00003

Cited by 371 publications

(220 citation statements)

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“…However, the inability of the HIV-D and HD groups to benefit from cuing to the same degree as the YHC group suggests that another factor, such as loss of remote memory, may also contribute to the RA pattern. Loss of remote memory in HD and HIV-D might reflect the diffuse cortical changes that occur in conjunction with subcortical gray and white matter pathology (de la Monte, Vonsattel, & Richardson, 1988;Jackson et al, 1995;Jernigan, Salmon, Butters, & Hesselink, 1991;McArthur, 1994;Navia et al, 1986;Rosas et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Retrograde Amnesia in Dementia: Comparison of HIV-Associated Dementia, Alzheimer's Disease, and Huntington's Disease.

et al. 2004

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Remote memory was assessed in persons with HIV-associated dementia (HIV-D), probable Alzheimer's disease (AD), and Huntington's disease (HD) and in healthy controls. The clinical groups were similar in overall dementia severity. Each clinical group exhibited impairments on remote memory tests relative to controls; however, temporally graded memory loss with selective preservation of older information was observed in the AD group but not the HD or HIV-D group. Analysis of cued retrieval indicated a preferential cuing benefit for the HIV-D and HD groups relative to the AD group. The similar pattern of remote memory performance demonstrated by the HIV-D and HD groups is a novel finding and suggests a subcortically mediated retrograde amnesia in HIV-D. The temporally graded pattern and the abnormal cued retrieval performance in the AD group are consistent with a consolidation deficit associated with extrahippocampal (cortical) and hippocampal damage.HIV is known to cause disorders of the central nervous system that may lead to cognitive impairment and, in a minority of cases, dementia (American Academy of Neurology AIDS Task Force, 1991;Grant & Martin, 1994). HIV-associated dementia (HIV-D) occurs in 7% to 14% of patients with AIDS (Grant & Martin, 1994). The clinical neuropsychological profile of persons infected with HIV, whether they exhibit dementia or minor cognitivemotor disorder (American Academy of Neurology AIDS Task Force, 1991), includes impairments in attention-working memory (

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Section: Discussionmentioning

confidence: 99%

Retrograde Amnesia in Dementia: Comparison of HIV-Associated Dementia, Alzheimer's Disease, and Huntington's Disease.

et al. 2004

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“…Wild-type STHdh Q7/Q7 and mutant STHdh Q111/Q111 striatal neuronal progenitor cells were washed once with phosphate-buffered saline (PBS), and total cellular proteins were extracted by incubating cells in lysis buffer containing 1% Triton X-100, 50 mM Tris-HCl (pH 7.5), 10 mM EGTA, 150 mM NaCl, protease inhibitors (2 mM phenylmethylsulfonyl fluoride (PMSF), 10 mg/ml aprotinin, 1 mg/ml leupeptin) and phosphatase inhibitors (2 mM Na 3 VO 4 , 100 mM NaF). Animals were deeply anesthetized and killed by decapitation at the age of 5 months (wild-type Hdh Q7/Q7 and mutant Hdh Q111/Q111 knock-in mice), 12 weeks (wild-type and R6/2 mice), 4,8,12,16,20 or 30 weeks (wild-type, R6/1, BDNF þ /À and R6/1 : BDNF þ /À mice) or 22 months (wild-type, gene-ON and gene-OFF Tet/ HD94 mice). The brain was quickly removed and the striatum, cortex and hippocampus were dissected out and homogenized in lysis buffer (as for cell protein extraction).…”

Section: Methodsmentioning

confidence: 99%

“…The more severe and early degeneration affects striatal projection neurons whereas loss of cortical neurons is observed at late stages of the disease. 4 The molecular basis that account for this specific neurodegeneration is still unknown, but different mechanisms have been proposed to contribute to the neurodegenerative process. 5 Mature neurons have the ability to activate survival mechanisms in response to harmful stimuli.…”

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confidence: 99%

PH domain leucine-rich repeat protein phosphatase 1 contributes to maintain the activation of the PI3K/Akt pro-survival pathway in Huntington's disease striatum

et al. 2009

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Dysregulation of gene expression is one of the mechanisms involved in the pathophysiology of Huntington's disease (HD). Here, we examined whether mutant huntingtin regulates the levels of PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1), a phosphatase that specifically dephosphorylates Akt at Ser473. Our results show decreased PHLPP1 protein levels in knock-in models (Hdh Q111/Q111 mouse striatum and STHdh Q111/Q111 cells), in the striatum of N-terminal exon-1 mutant huntingtin transgenic mouse models (R6/1; R6/1 : BDNF þ /À, R6/2 and Tet/HD94) and in the putamen of HD patients. Quantitative PCR analysis revealed a reduction in PHLPP1 mRNA levels in the striatum of R6/1 compared with wild-type mice. Coincident with reduced PHLPP1 protein levels, we observed increased phosphorylated Akt (Ser473) levels specifically in the striatum. The analysis of the conditional mouse model Tet/HD94 disclosed that after mutant huntingtin shutdown PHLPP1 levels returned to wild-type levels whereas phospho-Akt levels were partially reduced. In conclusion, our results show that mutant huntingtin downregulates PHLPP1 expression. In the striatum, these reduced levels of PHLPP1 can contribute to maintain high levels of activated Akt that may delay cell death and allow the recovery of neuronal viability after mutant huntingtin silencing.

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“…Ctip2 protein itself also is selectively expressed in striatal medium spiny neurons (29), the cell type uniquely lost in HD (2). The depletion of Ctip2 in the striatum, cortex, and hippocampus of R6/2 mice is consistent with the altered expression pattern of IPMK in these mice, which reflects the HD pathology in the cortex and additional brain tissues (30). Interestingly, Ctip2 overexpression in Q7 cells does not change IPMK protein levels, suggesting a potential negative feedback effect of IPMK or other targets on Ctip2 transcriptional activity.…”

Section: Discussionmentioning

confidence: 57%

Huntington’s disease: Neural dysfunction linked to inositol polyphosphate multikinase

Ahmed

Sbodio

Harraz

et al. 2015

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

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Huntington's disease (HD) is a progressive neurodegenerative disease caused by a glutamine repeat expansion in mutant huntingtin (mHtt). Despite the known genetic cause of HD, the pathophysiology of this disease remains to be elucidated. Inositol polyphosphate multikinase (IPMK) is an enzyme that displays soluble inositol phosphate kinase activity, lipid kinase activity, and various noncatalytic interactions. We report a severe loss of IPMK in the striatum of HD patients and in several cellular and animal models of the disease. This depletion reflects mHtt-induced impairment of COUP-TF-interacting protein 2 (Ctip2), a striatal-enriched transcription factor for IPMK, as well as alterations in IPMK protein stability. IPMK overexpression reverses the metabolic activity deficit in a cell model of HD. IPMK depletion appears to mediate neural dysfunction, because intrastriatal delivery of IPMK abates the progression of motor abnormalities and rescues striatal pathology in transgenic murine models of HD.Huntington's disease | inositol polyphosphate multikinase | IPMK | Ctip2 | Akt

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Morphometric Demonstration of Atrophic Changes in the Cerebral Cortex, White Matter, and Neostriatum in Huntington's Disease

Cited by 371 publications

References 0 publications

Retrograde Amnesia in Dementia: Comparison of HIV-Associated Dementia, Alzheimer's Disease, and Huntington's Disease.

Retrograde Amnesia in Dementia: Comparison of HIV-Associated Dementia, Alzheimer's Disease, and Huntington's Disease.

PH domain leucine-rich repeat protein phosphatase 1 contributes to maintain the activation of the PI3K/Akt pro-survival pathway in Huntington's disease striatum

Huntington’s disease: Neural dysfunction linked to inositol polyphosphate multikinase

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