The carboxypeptidase-like substrate-binding site in Nna1 is essential for the rescue of the Purkinje cell degeneration (pcd) phenotype

Wang, Taiyu; Parris, Jennifer; Li, Leyi; Morgan, James I.

doi:10.1016/j.mcn.2006.07.009

Cited by 52 publications

(100 citation statements)

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“…The spontaneous specific neuronal degeneration of PCs starts around postnatal day 20 (P20) and progresses rapidly over a 2-week period, resulting in a massive loss of PCs, together with neurological manifestations of cerebellar ataxia (11,12). In addition, retinal photoreceptors, mitral cells in the olfactory bulb, and a discrete population of thalamic neurons undergo late degeneration (13)(14)(15)(16).…”

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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

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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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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).…”

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confidence: 99%

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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“…Similarly, the homologous arginine residue R127 (numbered according to mature bovine carboxypeptides A1) in Caenorhabditis elegans AGBL4 (AGP/ GTP-binding-like protein 4) has been predicted to stabilize the oxyanion hole in the S1' site of the carboxypeptidase domain (Rodriguez de la Vega et al, 2007). Sequence comparison and structural modeling of sheep AGTPBP1 with other carboxypeptidases predicted R970 was located in a region known as the substratebinding pocket and catalytic center of metallocarboxypeptidase as mouse Nna1 (Supplementary Figure S3; Wang et al, 2006). These results enforce the view that R970 in sheep is a very conserved site being critical for its function of catalytic activity.…”

Section: Discussionmentioning

confidence: 55%

“…Features and conserved amino acids and motifs are located in similar positions. For example, the well-known zinc-binding HXXEyH motif lies between the second b-sheet and the first a-helix as reported (Wang et al, 2006). Six residues (His920, Glu923, Arg970, Asn979, Arg980 and Glu1102) remain conserved among these proteins (Supplementary Figure S3).…”

Section: Detection Of Identical By Descent (Ibd) Regionsmentioning

confidence: 79%

“…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%

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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 chemical complexity of cellular microtubules: Tubulin post‐translational modification enzymes and their roles in tuning microtubule functions

2012

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Cellular microtubules are marked by abundant and evolutionarily conserved post-translational modifications that have the potential to tune their functions. This review focuses on the astonishing chemical complexity introduced in the tubulin heterodimer at the post-translational level and summarizes the recent advances in identifying the enzymes responsible for these modifications and deciphering the consequences of tubulin’s chemical diversity on the function of molecular motors and microtubule associated proteins.

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The carboxypeptidase-like substrate-binding site in Nna1 is essential for the rescue of the Purkinje cell degeneration (pcd) phenotype

Cited by 52 publications

References 50 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

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

The chemical complexity of cellular microtubules: Tubulin post‐translational modification enzymes and their roles in tuning microtubule functions

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