Interaction of granule, Purkinje and inferior olivary neurons in lurcher chimeric mice. II. Granule cell death

Wetts, Richard; Herrup, Karl

doi:10.1016/0006-8993(82)90431-0

Cited by 213 publications

(95 citation statements)

References 11 publications

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“…4 F and J). This pattern corresponds to a general gradient laid down in the developing brain, whereby anterior regions develop marginally earlier than posterior ones, and is in keeping with the observation that anterior parts of the cerebellum are generally more susceptible to neurodegenerative processes, especially loss of Purkinje cells (36)(37)(38). At 28 weeks, Purkinje and granule cell loss as well as the extent of gliosis were no more severe than at 3 and 6 weeks (data not shown).…”

Section: Histopathology Of Tg L7dplsupporting

confidence: 86%

Transgene-driven expression of the Doppel protein in Purkinje cells causes Purkinje cell degeneration and motor impairment

Anderson

Rossi

Linehan

et al. 2004

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

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The Doppel (Dpl) and Prion (PrP) proteins show 25% sequence identity and share several structural features with only minor differences. Dpl shows a PrP-like fold of its C-terminal globular domain and lacks the flexible N-terminal tail. The physiological functions of both proteins are unknown. However, ubiquitous Dpl overexpression in the brain of PrP knockout mice correlated with ataxia and Purkinje cell degeneration in the cerebellum. Interestingly, a similar phenotype was reported in transgenic mice expressing an N-terminally truncated PrP (⌬PrP) in Purkinje cells by the L7 promoter (TgL7-⌬PrP). Coexpression of full-length PrP rescued both the neurological syndromes caused by either Dpl or ⌬PrP. To evaluate whether the two proteins caused cerebellar neurodegeneration by the same mechanism, we generated transgenic mice selectively expressing Dpl in Purkinje cells by the same L7 promoter. Such mice showed ataxia and Purkinje cell loss that depended on the level of Dpl expression. Interestingly, the effects of high levels of Dpl were not counterbalanced by the presence of two Prnp alleles. By contrast, PrP coexpression was sufficient to abrogate motor impairment and to delay the neurodegenerative process caused by moderate level of Dpl. A similar situation was reported for the corresponding TgL7-⌬PrP mice supporting the concept that Dpl and ⌬PrP cause cell death, possibly by interfering with a common signaling cascade essential for cell survival.

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Section: Histopathology Of Tg L7dplsupporting

confidence: 86%

Transgene-driven expression of the Doppel protein in Purkinje cells causes Purkinje cell degeneration and motor impairment

Anderson

Rossi

Linehan

et al. 2004

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

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“…When the Lurcher's Purkinje cells are mixed with normal Purkinje cells in the cerebellum of a Lurcher * wild type chimera formed by embryo aggregation techniques, only Purkinje cells carrying the Lurcher phenotype die during subsequent development; the wild-type Purkinje cells are left intact (Wetts and Hen-up, 1982). By contrast, inferior olivary neurons carrying the Lurcher phenotype survive in the chimeric inferior olivary complex, which maintains a mosaic of neurons with normal and mutant genotypes (Wetts and Herrup, 1982). The most likely explanation for the rescue of the Lurcher olivary neurons in the chimeric animals is the presence of neuronal targets in the chimeric cerebellum, i.e., the Purkinje cells contributed by the normal component of the chimera.…”

Section: Discussionmentioning

confidence: 99%

Expression of the weaver gene in dopamine-containing neural systems is dose-dependent and affects both striatal and nonstriatal regions

Roffler-Tarlov¹,

Graybiel²

1986

J. Neurosci.

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In an earlier report we presented evidence pointing to a differential effect of the mutant gene weaver on the dopamine-containing fiber systems innervating the striatum. In mice homozygous for the weaver mutation, there is a severe loss of dopamine in the caudoputamen, the main target of the nigrostriatal system. By contrast, dopamine is entirely conserved in the nucleus accumbens, a target of the mesolimbic system, and is moderately affected in the olfactory tubercle. The present study shows that these defects in dopamine are gene dose-dependent, that they are established by the end of the first month of life, and that the losses are permanent and not progressive. As in homozygous weavers, the greatest defects in striatal dopamine in heterozygous weavers occur in the dorsolateral caudoputamen and the lateral olfactory tubercle.The abnormalities in the striatal dopamine content of weaver mice are not accompanied by abnormalities in the turnover of dopamine, judging from measurements of the dopamine metabolite dihydroxyphenylacetic acid. Norepinephrine content is also normal in each striatal region. No deficits in striatal dopamine occur in mice homozygous for the mutant genes staggerer and Purkinje cell degeneration, which, like the weaver mutation, result in ataxia and cerebellar pathology.A survey of nonstriatal regions in the weaver mice showed that the effects of the weaver gene on the dopamine-containing innervation of the forebrain are not confined to striatal targets but also extend to the septum and the hypothalamus. By contrast, dopamine in the frontal cortex, the amygdala, the olfactory bulb, and the retina is entirely spared. The pattern and extent of loss of dopamine in the weaver forebrain is thus regionand system-specific. In confirmation of our initial findings, a ca. 30% depletion of dopamine occurs in the weaver midbrain, the region containing the cell bodies of origin of the mesostriatal dopamine systems. A comparison of histofluorescent sections through weaver and control midbrains revealed a reduction of catecholamine-containing neurons in the pars compacta of the weaver animals.These results point to a subpopulation of dopamine-containing neurons as primary targets of the weaver gene or as being closely associated with such primary targets. As a gene-dose effect has also been shown for the cerebellar granule cell loss in the weaver, the mutant gene must have at least 2 cellular Received Jan. 7, 1986; revised Apr. 30, 1986; accepted May 5, 1986. This work was supported by National Institutes of Health targets. We suggest that the cerebellar and mesostriatal pathologies may be linked by a common molecular mechanism.Two defects, one obvious and the other well hidden, are known to be present in the brains of mice that carry the autosomal recessive gene weaver. This mutation results in an atrophy of the cerebellum that is so severe in homozygous weavers that it can be detected after a glance at the intact brain. As was first reported by Sidman et al. in 1965, this macroscopic defect reflects an...

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“…Leaner mice lose granule neurons at about postnatal day 10 (Herrup & Wilczynski, 1982). Staggerer mice, lurcher mice ( Grid2 mutant), Purkinje cell degeneration mice, and astroglial Dicer knockout mice lose CGN secondary to Purkinje cell or astroglial abnormality (Wetts & Herrup, 1982; Herrup & Sunter, 1987; Wang & Morgan, 2007). Although these models are useful for studying cerebellar neurodevelopment, they are not suitable for studying age‐associated neurodegeneration.…”

Section: Introductionmentioning

confidence: 99%

The Immp2l mutation causes age‐dependent degeneration of cerebellar granule neurons prevented by antioxidant treatment

Liu

Lü

2015

Aging Cell

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SummaryReactive oxygen species are implicated in age‐associated neurodegeneration, although direct in vivo evidence is lacking. We recently showed that mice with a mutation in the Inner Mitochondrial Membrane Peptidase 2‐like (Immp2l) gene had elevated levels of mitochondrial superoxide, impaired fertility and age‐associated phenotypes, including kyphosis and ataxia. Here we show that ataxia and cerebellar hypoplasia occur in old mutant mice (> 16 months). Cerebellar granule neurons (CGNs) are significantly underrepresented; Purkinje cells and cells in the molecular layer are not affected. Treating mutant mice with the mitochondria‐targeted antioxidant SkQ1 from 6 weeks to 21 months protected cerebellar granule neurons. Apoptotic granule neurons were observed in mutant mice but not in age‐matched normal control mice or SkQ1‐treated mice. Old mutant mice showed increased serum protein carbonyl content, cerebellar 4‐hydroxynonenal (HNE), and nitrotyrosine modification compared to old normal control mice. SOD2 expression was increased in Purkinje cells but decreased in granule neurons of old mutant mice. Mitochondrial marker protein VDAC1 also was decreased in CGNs of old mutant mice, suggesting decreased mitochondrial number. SkQ1 treatment decreased HNE and nitrotyrosine modification, and restored SOD2 and VDAC1 expression in CGNs of old mutant mice. Neuronal expression of nitric oxide synthase was increased in cerebella of young mutant mice but decreased in old mutant mice. Our work provides evidence for a causal role of oxidative stress in neurodegeneration of Immp2l mutant mice. The Immp2l mutant mouse model could be valuable in elucidating the role of oxidative stress in age‐associated neurodegeneration.

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Interaction of granule, Purkinje and inferior olivary neurons in lurcher chimeric mice. II. Granule cell death

Cited by 213 publications

References 11 publications

Transgene-driven expression of the Doppel protein in Purkinje cells causes Purkinje cell degeneration and motor impairment

Transgene-driven expression of the Doppel protein in Purkinje cells causes Purkinje cell degeneration and motor impairment

Expression of the weaver gene in dopamine-containing neural systems is dose-dependent and affects both striatal and nonstriatal regions

The Immp2l mutation causes age‐dependent degeneration of cerebellar granule neurons prevented by antioxidant treatment

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