Trinucleotide (CAG) repeat length is positively correlated with the degree of DNA fragmentation in Huntington's disease striatum

Butterworth, N.J; Williams, Liam; Bullock, Jocelyn Y.; Love, Donald R.; Faull, Richard L.M.; Dragunow, Michael

doi:10.1016/s0306-4522(98)00129-8

Cited by 88 publications

(33 citation statements)

References 19 publications

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“…Very few TUNEL ϩ cells were present in the SEL in all HD cases examined. However, within the caudate nucleus there was a large number of TUNEL ϩ cells, as reported by Butterworth et al (8), but relatively few PCNA ϩ cells, suggesting that the PCNA antibody, in our studies, is labeling proliferating cells. The specificity of the PCNA antibody was also examined by subjecting SEL samples, extracted from control and HD brains, to Western blot analysis, and were immunoblotted with the PCNA antibody.…”

Section: Resultssupporting

confidence: 82%

Increased cell proliferation and neurogenesis in the adult human Huntington's disease brain

Curtis

Penney

Pearson

et al. 2003

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

490

342

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Neurogenesis has recently been observed in the adult human brain, suggesting the possibility of endogenous neural repair. However, the augmentation of neurogenesis in the adult human brain in response to neuronal cell loss has not been demonstrated. This study was undertaken to investigate whether neurogenesis occurs in the subependymal layer (SEL) adjacent to the caudate nucleus in the human brain in response to neurodegeneration of the caudate nucleus in Huntington's disease (HD). Postmortem control and HD human brain tissue were examined by using the cell cycle marker proliferating cell nuclear antigen (PCNA), the neuronal marker ␤III-tubulin, and the glial cell marker glial fibrillary acidic protein (GFAP). We observed a significant increase in cell proliferation in the SEL in HD compared with control brains. Within the HD group, the degree of cell proliferation increased with pathological severity and increasing CAG repeats in the HD gene. Most importantly, PCNA ؉ cells were shown to coexpress ␤III-tubulin or GFAP, demonstrating the generation of neurons and glial cells in the SEL of the diseased human brain. Our results provide evidence of increased progenitor cell proliferation and neurogenesis in the diseased adult human brain and further indicate the regenerative potential of the human brain.A particularly exciting development in the treatment of neurodegenerative diseases is the suggestion from both animal and human studies that transplantation of embryonic neurons or stem cells offer a potential treatment strategy for neurodegenerative disorders such as Parkinson's disease, Huntington's disease (HD), and Alzheimer's disease (1, 2). Although in recent years the transplantation of embryonic cells into the diseased human brain has emerged from the realm of the theoretical to that of the practical, it is associated with ethical, technical, and immunological problems (2). Thus, the demonstration of endogenous stem͞progenitor cells in the hippocampus and the subependymal layer (SEL) of the basal ganglia in the adult mammalian brain has raised the exciting possibility that these undifferentiated cells may be able to generate neurons for cell replacement in neurodegenerative diseases such as HD. Indeed, neural stem cells in the rodent brain SEL adjacent to the caudate nucleus have recently been shown to proliferate and differentiate into neurons (3-5), suggesting they may provide a source of replacement neurons. In this regard it is especially interesting that recent studies (6) on the normal adult human brain have shown evidence of neurogenesis in the hippocampus, but no previous study has yet shown neurogenesis in the SEL of the normal or diseased human brain. Here, we have examined whether progenitor cell proliferation and neurogenesis occur in the SEL adjacent to the caudate nucleus in response to cell death in the caudate nucleus of the adult human HD brain. The results demonstrate increased progenitor cell proliferation and neurogenesis in the SEL of the HD brains indicating that the diseased human brai...

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Section: Resultssupporting

confidence: 82%

Increased cell proliferation and neurogenesis in the adult human Huntington's disease brain

Curtis

Penney

Pearson

et al. 2003

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

490

342

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“…However, the elevation of fluorescence signal was relatively small, suggesting that only a limited proportion of cells synchronously died, consistent with the progressive aspect of degeneration in our model. Because this biochemical test based on caspase activity might not be sensitive enough to detect progressive degeneration, we next examined by FACS, in a large proportion of cultured cells (ϳ10,000 per culture well), nuclear DNA fragmentation, a hallmark of striatal degeneration in HD (Portera-Caillau et al, 1995;Thomas et al, 1995;Butterworth et al, 1998). In culture at 6 and 8 wk post infection, we counted cells positive for TUNEL staining, an in situ indicator of DNA fragmentation.…”

Section: Time Course Of Degeneration In Striatal Cells Expressing N-tmentioning

confidence: 99%

Involvement of Mitochondrial Complex II Defects in Neuronal Death Produced by N-Terminus Fragment of Mutated Huntingtin

Benchoua¹,

Trioulier²,

Zala

et al. 2006

MBoC

220

195

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Alterations of mitochondrial function may play a central role in neuronal death in Huntington's disease (HD). However, the molecular mechanisms underlying such functional deficits of mitochondria are not elucidated yet. We herein showed that the expression of two important constituents of mitochondrial complex II, the 30-kDa iron-sulfur (Ip) subunit and the 70-kDa FAD (Fp) subunit, was preferentially decreased in the striatum of HD patients compared with controls. We also examined several mitochondrial proteins in striatal neurons that were infected with lentiviral vectors coding for the N-terminus part of huntingtin (Htt) with either a pathological (Htt171-82Q) or physiological (Htt171-19Q) polyglutamine tract. Compared with Htt171-19Q, expression of Htt171-82Q preferentially decreased the levels of Ip and Fp subunits and affected the dehydrogenase activity of the complex. The Htt171-82Q-induced preferential loss of complex II was not associated with a decrease in mRNA levels, suggesting the involvement of a posttranscriptional mechanism. Importantly, the overexpression of either Ip or Fp subunit restored complex II levels and blocked mitochondrial dysfunction and striatal cell death induced by Htt171-82Q in striatal neurons. The present results strongly suggest that complex II defects in HD may be instrumental in striatal cell death. INTRODUCTIONHuntington's disease (HD) is a progressive neurodegenerative disorder caused by an abnormal expansion of a CAG repeat located in exon 1 of the gene encoding for the Huntingtin protein (Htt; The Huntington's Disease Collaborative Research Group, 1993). The mutation induces at least in part a loss of function, since wild-type Htt plays an important role in cell survival (Zuccato et al., 2003). In addition, the CAG repeat expansion leads to an abnormal polyglutamine (polyQ) tract that confers a new toxic function to full-length mutated Htt and/or short N-terminus fragments of the protein (Wellington et al., 2002;Li and Li, 2004). However, the mechanisms underlying the neuronal death induced by the polyQ expansion remain elusive.One hypothesis is that mitochondrial dysfunction is involved in striatal cell death in HD. HD patients display early striatal hypometabolism (for review, Beal, 1992), increase in lactate brain concentrations (Koroshetz et al., 1997;Jenkins et al., 1998), and reduced production of ATP in muscles (Lodi et al., 2000). Mitochondria isolated from cell expressing mutated Htt show decreased membrane potential, a defect in Ca 2ϩ homeostasis, and higher susceptibility to Ca 2ϩ -induced permeability transition (Panov et al., 2002;Choo et al., 2004).The mitochondrial hypothesis is also supported by the observation that systemic administration of the complex II inhibitor 3-nitropropionic acid (3NP) produces in rats and in nonhuman primates preferential degeneration of the striatum, abnormal movements, and frontal type cognitive deficits that are highly reminiscent of HD (for review Brouillet et al., 1999). In addition, complex II activity is severely impaired ...

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“…43 Mid-gestational exposure to chlorpyrifos, a cholinesterase-inhibiting pesticide, produced changes in proliferation, migration, and apoptosis in rat neuroepithelium. 44 Apoptosis is believed to underlie the pathogenesis of a number of human neurodegenerative diseases, including Alzheimer's disease (reviewed in 45,46 ), Huntington's disease, 47 Parkinson's disease, 48 and Down's syndrome. 49 In normal human development, cortical cell number is estimated to peak at 28 weeks of gestation, followed by a reduction in number by about 70% during the last quarter of prenatal development.…”

Section: Other Regionsmentioning

confidence: 99%

Qualitative and quantitative estimates of apoptosis from birth to senescence in the rat brain

White

Barone

2001

Cell Death Differ

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Apoptosis is crucial for proper development of the CNS, wherein a significant percentage of all central neurons produced during early ontogeny die by apoptosis. To characterize the pattern of developmental programmed cell death, we assayed rat brainstem, neocortex, hippocampus, and cerebellum from birth through senescence. Quantitatively, using an ELISA for oligonucleosomal DNA fragments, we demonstrated that PND1 brainstem, neocortex, and hippocampus have the highest levels of fragmented DNA compared to older ages. Cerebellum displayed a large peak at PND10 and a smaller peak at PND21. Low levels were observed throughout adulthood and into senescence, which was corroborated qualitatively by agarose gel and TUNEL data. These data provide a temporal and regional baseline for further studies of the effects of perturbations of cell death during neural development. Quantitative and qualitative changes in these regional profiles of apoptosis due to environmental insults during early ontogeny may alter neuron number and function later in life. Cell Death and Differentiation (2001) 8, 345 ± 356.

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Trinucleotide (CAG) repeat length is positively correlated with the degree of DNA fragmentation in Huntington's disease striatum

Cited by 88 publications

References 19 publications

Increased cell proliferation and neurogenesis in the adult human Huntington's disease brain

Increased cell proliferation and neurogenesis in the adult human Huntington's disease brain

Involvement of Mitochondrial Complex II Defects in Neuronal Death Produced by N-Terminus Fragment of Mutated Huntingtin

Qualitative and quantitative estimates of apoptosis from birth to senescence in the rat brain

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