Characterisation of PGs1, a subunit of a protein complex co-purifying with tubulin polyglutamylase.

Centre de Recherches de Biochimie Macromoléculaire, CNRS, 34293 Montpellier, France.
Journal of Cell Science (Impact Factor: 5.33). 11/2003; 116(Pt 20):4181-90. DOI: 10.1242/jcs.00743
Source: PubMed

ABSTRACT Polyglutamylation is a post-translational modification initially discovered on tubulin. It has been implicated in multiple microtubule functions, including neuronal differentiation, axonemal beating and stability of the centrioles, and shown to modulate the interaction between tubulin and microtubule associated proteins. The enzymes catalysing this modification are not yet known. Starting with a partially purified fraction of mouse brain tubulin polyglutamylase, monoclonal antibodies were raised and used to further purify the enzyme by immunoprecipitation. The purified enzyme complex (Mr 360x103) displayed at least three major polypeptides of 32, 50 and 80x103, present in stochiometric amounts. We show that the 32x103 subunit is encoded by the mouse gene GTRGEO22, the mutation of which has recently been implicated in multiple defects in mice, including male sterility. We demonstrate that this subunit, called PGs1, has no catalytic activity on its own, but is implicated in the localisation of the enzyme at major sites of polyglutamylation, i.e. neurones, axonemes and centrioles.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Amyotrophic lateral sclerosis is heterogeneous with high variability in the speed of progression even in cases with a defined genetic cause such as superoxide dismutase 1 (SOD1) mutations. We reported that SOD1(G93A) mice on distinct genetic backgrounds (C57 and 129Sv) show consistent phenotypic differences in speed of disease progression and life-span that are not explained by differences in human SOD1 transgene copy number or the burden of mutant SOD1 protein within the nervous system. We aimed to compare the gene expression profiles of motor neurons from these two SOD1(G93A) mouse strains to discover the molecular mechanisms contributing to the distinct phenotypes and to identify factors underlying fast and slow disease progression. Lumbar spinal motor neurons from the two SOD1(G93A) mouse strains were isolated by laser capture microdissection and transcriptome analysis was conducted at four stages of disease. We identified marked differences in the motor neuron transcriptome between the two mice strains at disease onset, with a dramatic reduction of gene expression in the rapidly progressive (129Sv-SOD1(G93A)) compared with the slowly progressing mutant SOD1 mice (C57-SOD1(G93A)) (1276 versus 346; Q-value ≤ 0.01). Gene ontology pathway analysis of the transcriptional profile from 129Sv-SOD1(G93A) mice showed marked downregulation of specific pathways involved in mitochondrial function, as well as predicted deficiencies in protein degradation and axonal transport mechanisms. In contrast, the transcriptional profile from C57-SOD1(G93A) mice with the more benign disease course, revealed strong gene enrichment relating to immune system processes compared with 129Sv-SOD1(G93A) mice. Motor neurons from the more benign mutant strain demonstrated striking complement activation, over-expressing genes normally involved in immune cell function. We validated through immunohistochemistry increased expression of the C3 complement subunit and major histocompatibility complex I within motor neurons. In addition, we demonstrated that motor neurons from the slowly progressing mice activate a series of genes with neuroprotective properties such as angiogenin and the nuclear factor (erythroid-derived 2)-like 2 transcriptional regulator. In contrast, the faster progressing mice show dramatically reduced expression at disease onset of cell pathways involved in neuroprotection. This study highlights a set of key gene and molecular pathway indices of fast or slow disease progression which may prove useful in identifying potential disease modifiers responsible for the heterogeneity of human amyotrophic lateral sclerosis and which may represent valid therapeutic targets for ameliorating the disease course in humans.
    Brain 09/2013; · 10.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In 1902, the lethal yellow or Agouti yellow (A y ) mouse was described by French geneticist Lucien Cuenot in a paper detailing coat-color inheritance in mice. Although the Agouti mouse reportedly had been bred by European mouse fanciers since the 1800s, the phenotype of obesity was not published until 1927. In the late 1960s, the obese (ob/ob) and diabetic (db/db) mouse models were described. All three of these models have been widely used in obesity research since that time. With the advent of technologies to create transgenic and knockout strains of mice there has been a rapid increase in the number of mice displaying different defects in body weight regulation. This chapter will categorize the more than 200 mouse models of body weight disorders that now exist, more than 100 years after the agouti yellow mouse was first characterized. The Obesity Gene map database ( is updated yearly and is a thorough reference for all genes and loci, both rodent and human, known to modulate body weight or energy utilization. This chapter categorizes mouse models listed in that database, and includes recently published models in five groupings: juvenile-onset obese models, adult-onset obese models, obesity-resistant models, polygenic obese models, and models with altered responses to induced obesity.
    12/2007: pages 683-702;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Microtubules are cytoskeletal filaments that are dynamically assembled from α/β-tubulin heterodimers. The primary sequence and structure of the tubulin proteins and, consequently, the properties and architecture of microtubules are highly conserved in eukaryotes. Despite this conservation, tubulin is subject to heterogeneity that is generated in two ways: by the expression of different tubulin isotypes and by posttranslational modifications (PTMs). Identifying the mechanisms that generate and control tubulin heterogeneity and how this heterogeneity affects microtubule function are long-standing goals in the field. Recent work on tubulin PTMs has shed light on how these modifications could contribute to a "tubulin code" that coordinates the complex functions of microtubules in cells.
    The Journal of Cell Biology 08/2014; 206(4):461-472. · 9.69 Impact Factor


Available from
May 31, 2014