The Purkinje cell degeneration (pcd) mouse: An unexpected molecular link between neuronal degeneration and regeneration

Wang, Taiyu; Morgan, James I.

doi:10.1016/j.brainres.2006.07.065

Cited by 81 publications

(176 citation statements)

References 81 publications

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“…Given that in the cerebellar cortex of pcd mice at P20 both healthy PCs and PCs undergoing different stages of neuronal degeneration coexist, we selected this postnatal day to study the reorganization of the nuclear architecture that is associated with this type of neurodegeneration. At this postnatal stage, the granule cell layer was well preserved, and no cytological signs of granule cell degeneration were observed, as described previously (18).…”

Section: Resultssupporting

confidence: 79%

“…In addition, retinal photoreceptors, mitral cells in the olfactory bulb, and a discrete population of thalamic neurons undergo late degeneration (13)(14)(15)(16). In pcd mice, only the nna1 gene is affected (17,18). This gene encodes a protein, Nna1, with a putative zinc carboxypeptidase domain, which is essential for PC survival (12,18).…”

mentioning

confidence: 99%

“…In pcd mice, only the nna1 gene is affected (17,18). This gene encodes a protein, Nna1, with a putative zinc carboxypeptidase domain, which is essential for PC survival (12,18). Nna1 contains nuclear localization signals and is localized in both the nucleus and cytoplasm (19).…”

mentioning

confidence: 99%

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Purkinje Cell Degeneration in pcd Mice Reveals Large Scale Chromatin Reorganization and Gene Silencing Linked to Defective DNA Repair

Baltanás

Casafont

Lafarga

et al. 2011

Journal of Biological Chemistry

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DNA repair protects neurons against spontaneous or diseaseassociated DNA damage. Dysfunctions of this mechanism underlie a growing list of neurodegenerative disorders. The Purkinje cell (PC) degeneration mutation causes the loss of nna1 expression and is associated with the postnatal degeneration of PCs. This PC degeneration dramatically affects nuclear architecture and provides an excellent model to elucidate the nuclear mechanisms involved in a whole array of neurodegenerative disorders. We used immunocytochemistry for histone variants and components of the DNA damage response, an in situ transcription assay, and in situ hybridization for telomeres to analyze changes in chromatin architecture and function. We demonstrate that the phosphorylation of H2AX, a DNA damage signal, and the trimethylation of the histone H4K20, a repressive mark, in extensive domains of genome are epigenetic hallmarks of chromatin in degenerating PCs. These histone modifications are associated with a large scale reorganization of chromatin, telomere clustering, and heterochromatin-induced gene silencing, all of them key factors in PC degeneration. Furthermore, ataxia telangiectasia mutated and 53BP1, two components of the DNA repair pathway, fail to be concentrated in the damaged chromatin compartments, even though the expression levels of their coding genes were slightly up-regulated. Although the mechanism by which Nna1 loss of function leads to PC neurodegeneration is undefined, the progressive accumulation of DNA damage in chromosome territories irreversibly compromises global gene transcription and seems to trigger PC degeneration and death.

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Section: Resultssupporting

confidence: 79%

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confidence: 99%

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Purkinje Cell Degeneration in pcd Mice Reveals Large Scale Chromatin Reorganization and Gene Silencing Linked to Defective DNA Repair

Baltanás

Casafont

Lafarga

et al. 2011

Journal of Biological Chemistry

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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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“…A total of 12 alleles in mouse mutants related to Agtpbp1 have been summarized by the Jackson Laboratory (http:// www.informatics.jax.org/searches/allele_report.cgi?_Marker_key=79447). Among which, loss-of-function of Agtpbp1 was indicated as being responsible for pcd 3J and pcd 5J mouse mutants (Fernandez-Gonzalez, et al, 2002;Wang and Morgan, 2007;Chakrabarti et al, 2008). Expression of full-length Nna1 successfully rescued Purkinje cell loss and ataxic behavior in pcd 3J , and retinal photoreceptor loss and pcd in pcd 5J mice (Wang et al 2006, Chakrabarti et al, 2008.…”

Section: Discussionmentioning

confidence: 99%

A missense mutation in AGTPBP1 was identified in sheep with a lower motor neuron disease

et al. 2012

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A type of lower motor neuron (LMN) disease inherited as autosomal recessive in Romney sheep was characterized with normal appearance at birth, but with progressive weakness and tetraparesis after the first week of life. Here, we carried out genomewide homozygosity mapping using Illumina Ovine SNP50 BeadChips on lambs descended from one carrier ram, including 19 sheep diagnosed as affected and 11 of their parents that were therefore known carriers. A homozygous region of 136 consecutive single-nucleotide polymorphism (SNP) loci on chromosome 2 was common to all affected sheep and it was the basis for searching for the positional candidate genes. Other homozygous regions shared by all affected sheep spanned eight or fewer SNP loci. The 136-SNP region contained the sheep ATP/GTP-binding protein 1 (AGTPBP1) gene. Mutations in this gene have been shown to be related to Purkinje cell degeneration (pcd) phenotypes including ataxia in mice. One missense mutation c.2909G4C on exon 21 of AGTPBP1 was discovered, which induces an Arg to Pro substitution (p.Arg970Pro) at amino-acid 970, a conserved residue for the catalytic activity of AGTPBP1. Genotyping of this mutation showed 100% concordant rate with the recessive pattern of inheritance in affected, carrier, phenotypically normal and unrelated normal individuals. This is the first report showing a mutant AGTPBP1 is associated with a LMN disease in a large mammal animal model. Our finding raises the possibility of human patients with the same etiology caused by this gene or other genes in the same pathway of neuronal development.

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The Purkinje cell degeneration (pcd) mouse: An unexpected molecular link between neuronal degeneration and regeneration

Cited by 81 publications

References 81 publications

Purkinje Cell Degeneration in pcd Mice Reveals Large Scale Chromatin Reorganization and Gene Silencing Linked to Defective DNA Repair

Purkinje Cell Degeneration in pcd Mice Reveals Large Scale Chromatin Reorganization and Gene Silencing Linked to Defective DNA Repair

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

A missense mutation in AGTPBP1 was identified in sheep with a lower motor neuron disease

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