scholarly journals Loss of the golgin GM130 causes Golgi disruption, Purkinje neuron loss, and ataxia in mice

2016 ◽  
Vol 114 (2) ◽  
pp. 346-351 ◽  
Author(s):  
Chunyi Liu ◽  
Mei Mei ◽  
Qiuling Li ◽  
Peristera Roboti ◽  
Qianqian Pang ◽  
...  
Keyword(s):  
Golgi Apparatus ◽  
Purkinje Cell ◽  
Secretory Pathway ◽  
Neuronal Degeneration ◽  
Cell Loss ◽  
Cell Number ◽  
Causative Role ◽  
Neurodegenerative Process ◽  
And Function

The Golgi apparatus lies at the heart of the secretory pathway where it is required for secretory trafficking and cargo modification. Disruption of Golgi architecture and function has been widely observed in neurodegenerative disease, but whether Golgi dysfunction is causal with regard to the neurodegenerative process, or is simply a manifestation of neuronal death, remains unclear. Here we report that targeted loss of the golgin GM130 leads to a profound neurological phenotype in mice. Global KO of mouse GM130 results in developmental delay, severe ataxia, and postnatal death. We further show that selective deletion of GM130 in neurons causes fragmentation and defective positioning of the Golgi apparatus, impaired secretory trafficking, and dendritic atrophy in Purkinje cells. These cellular defects manifest as reduced cerebellar size and Purkinje cell number, leading to ataxia. Purkinje cell loss and ataxia first appear during postnatal development but progressively worsen with age. Our data therefore indicate that targeted disruption of the mammalian Golgi apparatus and secretory traffic results in neuronal degeneration in vivo, supporting the view that Golgi dysfunction can play a causative role in neurodegeneration.

scholarly journals Centriole Disassembly In Vivo and Its Effect on Centrosome Structure and Function in Vertebrate Cells

1998 ◽  
Vol 143 (6) ◽  
pp. 1575-1589 ◽  
Author(s):  
Y. Bobinnec ◽  
A. Khodjakov ◽  
L.M. Mir ◽  
C.L. Rieder ◽  
B. Eddé ◽  
...  
Keyword(s):  
Posttranslational Modification ◽  
Electron Microscopic Observation ◽  
Cell Number ◽  
Animal Cells ◽  
Electron Microscopic ◽  
Long Term Stability ◽  
Pericentriolar Material ◽  
Immunofluorescence Labeling ◽  
And Function

Glutamylation is the major posttranslational modification of neuronal and axonemal tubulin and is restricted predominantly to centrioles in nonneuronal cells (Bobinnec, Y., M. Moudjou, J.P. Fouquet, E. Desbruyères, B. Eddé, and M. Bornens. 1998. Cell Motil. Cytoskel. 39:223–232). To investigate a possible relationship between the exceptional stability of centriole microtubules and the compartmentalization of glutamylated isoforms, we loaded HeLa cells with the monoclonal antibody GT335, which specifically reacts with polyglutamylated tubulin. The total disappearance of the centriole pair was observed after 12 h, as judged both by immunofluorescence labeling with specific antibodies and electron microscopic observation of cells after complete thick serial sectioning. Strikingly, we also observed a scattering of the pericentriolar material (PCM) within the cytoplasm and a parallel disappearance of the centrosome as a defined organelle. However, centriole disappearance was transient, as centrioles and discrete centrosomes ultimately reappeared in the cell population. During the acentriolar period, a large proportion of monopolar half-spindles or of bipolar spindles with abnormal distribution of PCM and NuMA were observed. However, as judged by a quasinormal increase in cell number, these cells likely were not blocked in mitosis. Our results suggest that a posttranslational modification of tubulin is critical for long-term stability of centriolar microtubules. They further demonstrate that in animal cells, centrioles are instrumental in organizing centrosomal components into a structurally stable organelle.

scholarly journals Bacterial Outer Membrane Ushers Contain Distinct Targeting and Assembly Domains for Pilus Biogenesis

2002 ◽  
Vol 184 (22) ◽  
pp. 6260-6269 ◽  
Author(s):  
David G. Thanassi ◽  
Christos Stathopoulos ◽  
Karen Dodson ◽  
Dominik Geiger ◽  
Scott J. Hultgren
Keyword(s):  
Outer Membrane ◽  
Secretory Pathway ◽  
Terminal Branch ◽  
C Terminus ◽  
Type 1 Pili ◽  
Pilus Biogenesis ◽  
And Function

ABSTRACT Biogenesis of a superfamily of surface structures by gram-negative bacteria requires the chaperone/usher pathway, a terminal branch of the general secretory pathway. In this pathway a periplasmic chaperone works together with an outer membrane usher to direct substrate folding, assembly, and secretion to the cell surface. We analyzed the structure and function of the PapC usher required for P pilus biogenesis by uropathogenic Escherichia coli. Structural analysis indicated PapC folds as a β-barrel with short extracellular loops and extensive periplasmic domains. Several periplasmic regions were localized, including two domains containing conserved cysteine pairs. Functional analysis of deletion mutants revealed that the PapC C terminus was not required for insertion of the usher into the outer membrane or for proper folding. The usher C terminus was not necessary for interaction with chaperone-subunit complexes in vitro but was required for pilus biogenesis in vivo. Interestingly, coexpression of PapC C-terminal truncation mutants with the chromosomal fim gene cluster coding for type 1 pili allowed P pilus biogenesis in vivo. These studies suggest that chaperone-subunit complexes target an N-terminal domain of the usher and that subunit assembly into pili depends on a subsequent function provided by the usher C terminus.

scholarly journals SlamHaplotypes Modulate the Response to Lipopolysaccharide In Vivo through Control of NKT Cell Number and Function

2010 ◽  
Vol 185 (1) ◽  
pp. 144-156 ◽  
Author(s):  
Idil Aktan ◽  
Alan Chant ◽  
Zachary D. Borg ◽  
David E. Damby ◽  
Paige C. Leenstra ◽  
...  
Keyword(s):  
Cell Number ◽  
Nkt Cell ◽  
And Function

scholarly journals Targeting VE-PTP phosphatase protects the kidney from diabetic injury

2019 ◽  
Vol 216 (4) ◽  
pp. 936-949 ◽  
Author(s):  
Isabel A. Carota ◽  
Yael Kenig-Kozlovsky ◽  
Tuncer Onay ◽  
Rizaldy Scott ◽  
Benjamin R. Thomson ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Tyrosine Phosphatase ◽  
Hypoxia Inducible Factor ◽  
Cell Loss ◽  
Tie2 Receptor ◽  
Nuclear Exclusion ◽  
Promising Therapeutic Target ◽  
End Stage ◽  
And Function

Diabetic nephropathy is a leading cause of end-stage kidney failure. Reduced angiopoietin-TIE2 receptor tyrosine kinase signaling in the vasculature leads to increased vascular permeability, inflammation, and endothelial cell loss and is associated with the development of diabetic complications. Here, we identified a mechanism to explain how TIE2 signaling is attenuated in diabetic animals. Expression of vascular endothelial protein tyrosine phosphatase VE-PTP (also known as PTPRB), which dephosphorylates TIE2, is robustly up-regulated in the renal microvasculature of diabetic rodents, thereby reducing TIE2 activity. Increased VE-PTP expression was dependent on hypoxia-inducible factor transcriptional activity in vivo. Genetic deletion of VE-PTP restored TIE2 activity independent of ligand availability and protected kidney structure and function in a mouse model of severe diabetic nephropathy. Mechanistically, inhibition of VE-PTP activated endothelial nitric oxide synthase and led to nuclear exclusion of the FOXO1 transcription factor, reducing expression of pro-inflammatory and pro-fibrotic gene targets. In sum, we identify inhibition of VE-PTP as a promising therapeutic target to protect the kidney from diabetic injury.

Insights into the Secretory Pathway, the Mechanism of Terminal Glycosylation and Intracellular Peptide Hormone Receptors from Studies on Hepatic Golgi Fractions

1981 ◽  
Vol 39 ◽  
pp. 516-519
Author(s):  
J.J.M. Bergeron ◽  
B.I. Posner ◽  
Jacques Paiement ◽  
R. Sikstrom ◽  
M. Khan
Keyword(s):  
Golgi Apparatus ◽  
Plasma Proteins ◽  
Secretory Pathway ◽  
Hormone Receptors ◽  
Peptide Hormone ◽  
Secretory Protein ◽  
Golgi Membrane ◽  
Membrane Structures

Recent studies on purified subcellular fractions of hepatic Golgi apparatus have provided insight into the functioning of the Golgi apparatus in vivo.The hepatocyte is the site of synthesis of most circulating plasma proteins. On a total protein basis, purified Golgi fractions revealed mainly secretory content (albumin, transferrin and other plasma proteins) as major constituents. After an in vivo injection of radiolabeled leucine, newly synthesized secretory protein followed a temporal route from cis to trans regions of Golgi apparatus before appearance in the plasma. This route was revealed by studies on disrupted Golgi fractions enriched in disparate regions of the Golgi apparatus.The terminal glycosylation of secretory glcyoproteins (e.g. transferrin) can be studied by observing the transfer of UDP-(3H)-galactose to endogenous acceptors within Golgi fractions. Transfer was shown to occur to a glycolipid (dolichyl galactosyl phosphate) probably on the cytosolic aspect of the Golgi membrane. Translocation of the labeled galactose across the membrane coincided with fusion of Golgi saccules in vitro. It is felt that during the process of Golgi membrane fusion, inverted lipid- micellar membrane structures translocate the dolichyl galactosyl phosphate from a cytosolic to a luminal orientation. Luminally oriented dolichyl galactosyl phosphate would then serve as substrate for galactose transfer to intraluminal glycopeptide acceptors via intraluminal galactosyl transferase enzyme.

The response of the brachial ventral horn of Xenopus laevis to forelimb amputation during development

Development ◽  
1976 ◽  
Vol 36 (3) ◽  
pp. 453-468
Author(s):  
Joanne E. Fortune ◽  
Antonie W. Blackler
Keyword(s):  
Xenopus Laevis ◽  
Normal Development ◽  
Developmental Stages ◽  
Neuronal Degeneration ◽  
Neuronal Loss ◽  
Cell Loss ◽  
Cell Number ◽  
Ventral Horn ◽  
Cell Degeneration ◽  
Cell Numbers

The normal development of the brachial ventral horn of the frog Xenopus laevis and the response of the brachial ventral horn to complete forelimb extirpation at five developmental stages were assessed histologically. Differentiation of brachial ventral horn neurons occurred in pre-metamorphic tadpoles between stages 52/53 and 57. Mean cell number in the brachial ventral horn reached a peak of 2576 (S.E.M. = ±269, n = 2) per side of the spinal cord at stage 55 and decreased to 1070 (S.E.M. = ± 35, n =7) by the end of metamorphosis. Cell degeneration was presumed to be the mode of cell loss since it was most prevalent during the period of rapid decrease in cell numbers. The response of the ventral horn to forelimb removal varied with the stage of the animal at amputation. Following amputation at stage 52/53 or 54 the ipsilateral ventral horn neurons appeared less differentiated than those on the controlside and a rapid cell loss of about 80 % occurred on the operated side. These effects occurred more rapidly after ablation at stage 54 than at stage 52/53. Amputation at stage 58, 61, or 66 caused chromatolysis in the ventral horn, a period of relative cell excess on the operated side, and a delayed neuronal loss of 32–66%. It was concluded that excess cell degeneration accounted for cell loss and that suppression of normal neuronal degeneration caused the relative cell excess on the operated side. The data indicate that the brachial ventral horn was indifferent to the periphery before stage 54, was quickly affected by limb removal between stages 54 and 58, and by stage 58 had entered a phase in which a delay preceded cell death. No forelimb regeneration occurred.

scholarly journals Inhibition of the Secretory Pathway by Foot-and-Mouth Disease Virus 2BC Protein Is Reproduced by Coexpression of 2B with 2C, and the Site of Inhibition Is Determined by the Subcellular Location of 2C

2006 ◽  
Vol 81 (3) ◽  
pp. 1129-1139 ◽  
Author(s):  
Katy Moffat ◽  
Caroline Knox ◽  
Gareth Howell ◽  
Sarah J. Clark ◽  
H. Yang ◽  
...  
Keyword(s):  
Golgi Apparatus ◽  
Immune Responses ◽  
Disease Virus ◽  
Secretory Pathway ◽  
Protein Transport ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Mouth Disease Virus ◽  
Foot And Mouth

ABSTRACT Infection of cells with picornaviruses can lead to a block in protein secretion. For poliovirus this is achieved by the 3A protein, and the consequent reduction in secretion of proinflammatory cytokines and surface expression of major histocompatibility complex class I proteins may inhibit host immune responses in vivo. Foot-and-mouth disease virus (FMDV), another picornavirus, can cause persistent infection of ruminants, suggesting it too may inhibit immune responses. Endoplasmic reticulum (ER)-to-Golgi apparatus transport of proteins is blocked by the FMDV 2BC protein. The observation that 2BC is processed to 2B and 2C during infection and that individual 2B and 2C proteins are unable to block secretion stimulated us to study the effects of 2BC processing on the secretory pathway. Even though 2BC was processed rapidly to 2B and 2C, protein transport to the plasma membrane was still blocked in FMDV-infected cells. The block could be reconstituted by coexpression of 2B and 2C, showing that processing of 2BC did not compromise the ability of FMDV to slow secretion. Under these conditions, 2C was located to the Golgi apparatus, and the block in transport also occurred in the Golgi apparatus. Interestingly, the block in transport could be redirected to the ER when 2B was coexpressed with a 2C protein fused to an ER retention element. Thus, for FMDV a block in secretion is dependent on both 2B and 2C, with the latter determining the site of the block.

scholarly journals Oligomerization of Lrrk controls actin severing and α-synuclein neurotoxicity in vivo

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Souvarish Sarkar ◽  
Farah Bardai ◽  
Abby L. Olsen ◽  
Kelly M. Lohr ◽  
Ying-Yi Zhang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Degeneration ◽  
Mitochondrial Dynamics ◽  
Actin Dynamics ◽  
Human Neurons ◽  
Biochemical Analyses ◽  
And Function

Abstract Background Mutations in LRRK2 are the most common cause of familial Parkinson’s disease and typically cause disease in the context of abnormal aggregation and deposition of α-synuclein within affected brain tissue. Methods We combine genetic analysis of Lrrk-associated toxicity in a penetrant Drosophila model of wild type human α-synuclein neurotoxicity with biochemical analyses and modeling of LRRK2 toxicity in human neurons and transgenic mouse models. Results We demonstrate that Lrrk and α-synuclein interact to promote neuronal degeneration through convergent effects on the actin cytoskeleton and downstream dysregulation of mitochondrial dynamics and function. We find specifically that monomers and dimers of Lrrk efficiently sever actin and promote normal actin dynamics in vivo. Oligomerization of Lrrk, which is promoted by dominant Parkinson’s disease-causing mutations, reduces actin severing activity in vitro and promotes excess stabilization of F-actin in vivo. Importantly, a clinically protective Lrrk mutant reduces oligomerization and α-synuclein neurotoxicity. Conclusions Our findings provide a specific mechanistic link between two key molecules in the pathogenesis of Parkinson’s disease, α-synuclein and LRRK2, and suggest potential new approaches for therapy development.

scholarly journals Golgi apparatus-targeted AIEgens for effective photodynamic therapy through the crosstalk of Golgi apparatus and mitochondria

2021 ◽  
Author(s):  
Minglun Liu ◽  
Yuncong Chen ◽  
Yan Guo ◽  
Hao Yuan ◽  
Shankun Yao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Photodynamic Therapy ◽  
Golgi Apparatus ◽  
Pearson Correlation ◽  
Design Strategy ◽  
Apoptotic Pathway ◽  
Oxygen Generation ◽  
Targeting Ability ◽  
And Function

Abstract Golgi apparatus (GA) oxidative stress induced by in situ reactive oxygen species (ROS) could severely damage the morphology and function of GA, which may open up a new avenue for effective photodynamic therapy (PDT). However, due to the lack of effective design strategy, photosensitizers (PSs) with specific GA targeting ability have not been reported. Herein, we report aggregation-induced emission luminogen (AIEgen) based PSs that can effectively target to GA with Pearson correlation coefficient (PCC) up to 0.98 and singlet oxygen generation rate up to 77.8%. GA fragmentation and cleavage of GA proteins (p115/GM130) were observed upon light irradiation. Meanwhile, the apoptotic pathway was activated through a crosstalk between GA oxidative stress and mitochondria in HeLa cells. Finally, TPE-PyT-CPS can effectively inhibited tumour growth in vivo with negligible adverse effect. This work provided a promising design strategy for the development of PSs with specific GA targeting ability, which is of great importance for precise and effective PDT.

A New Working Hypothesis for the Structure and Function of the Golgi Apparatus in Plant Cell Wall Biogenesis

1973 ◽  
Vol 31 ◽  
pp. 456-457 ◽  
Author(s):  
R. Malcolm Brown
Keyword(s):  
Golgi Apparatus ◽  
Plant Cell Wall ◽  
Higher Plants ◽  
Synthetase Activity ◽  
Higher Plant ◽  
General Belief ◽  
Glucan Synthetase ◽  
And Function

It is the general belief of many investigators that the pathway of cellulose biogenesis occurs via soluble pools of hexose phosphate monomers and the plasma membrane which is thought to be the site of polymerization and/or crystalization. Brown and coworkers and Ray (see 1) have proposed to the contrary that the Golgi apparatus is the site of cellulose biogenesis in certain scale-producing algae and higher plants respectively. While it has been fairly well established that cellulose can be biosynthesized by the Golgi apparatus, considerable doubt has been expressed that this type of system could be applicable to cellulose biogenesis in higher plant systems. Conversely, the problems associated with in vitro cellulose biosynthesis in Golgi-enriched homogenates raises questions about the in vivo localization of B-(1,4)-glucan synthetase activity.

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