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11 results on '"Bradshaw, Teisha Y."'

1. The cellular phenotype of the neurodegenerative disease autosomal recessive spastic ataxia of Charlevoix-Saguenay

Author

Bradshaw, Teisha Y.

Subjects
616.8, Medicine, Endocrinology, Autosomal recessive spastic ataxia of Charlevoix Saguenay, Neurodegenerative diseases, SACS gene, Sacsin
Abstract

Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) is an early onset neurodegenerative disorder resulting from mutations in the SACS gene that encodes the protein sacsin. Sacsin is a 520kDa multi-domain protein localised at the cytosolic face of the outer mitochondrial membrane with suggested roles in proteostasis and most recently in the regulation of mitochondrial morphology. An excessively interconnected mitochondrial network was observed as a consequence of reduced levels of sacsin protein following SACS knockdown in neuroblastoma cells as well as in an ARSACS patient carrying the common Quebec homozygous SACS mutation 8844delT. Moreover, it was suggested that sacsin has a role in mitochondrial fission as it was found to interact with mitochondrial fission protein Dynamin related protein 1 (Drp1). The aim of this thesis was to explore sacsin’s role in the regulation of mitochondrial morphology and dynamics in non-Quebec ARSACS patients and sacsin knockdown fibroblasts. This study shows that loss of sacsin function promotes a more interconnected mitochondrial network in non-Quebec ARSACS patients and in sacsin knockdown fibroblasts. Moreover, recruitment of the essential mitochondrial fission protein Drp1 to the mitochondria was significantly reduced in ARSACS patient cells and in sacsin knockdown fibroblasts. This reduced recruitment of Drp1 to mitochondria also occurred when cells were treated to induce mitochondrial fission. Furthermore, both the size and intensity of Drp1 foci localised to the mitochondria were significantly reduced in both sacsin knockdown and patient fibroblasts. Finally, reduced ATP production, decreased respiratory capacity of mitochondria and an increase in mitochondrial reactive oxygen species demonstrated impaired mitochondrial function in ARSACS patient and sacsin knockdown fibroblasts. These results suggest a role for sacsin in the stabilisation or recruitment of cytoplasmic Drp1 to prospective sites of mitochondrial fission similar to that observed by other mitochondrial fission accessory proteins.

Published
2014

3. Gain-of-Function Mutations of ARHGAP31, a Cdc42/Rac1 GTPase Regulator, Cause Syndromic Cutis Aplasia and Limb Anomalies

Author

Southgate, Laura, Machado, Rajiv D., Snape, Katie M., Primeau, Martin, Dafou, Dimitra, Ruddy, Deborah M., Branney, Peter A., Fisher, Malcolm, Lee, Grace J., Simpson, Michael A., He, Yi, Bradshaw, Teisha Y., Blaumeiser, Bettina, Winship, William S., Reardon, Willie, Maher, Eamonn R., FitzPatrick, David R., Wuyts, Wim, Zenker, Martin, Lamarche-Vane, Nathalie, and Trembath, Richard C.

Published
2011
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4. Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension

Author

Nasim, Md. Talat, Ogo, Takeshi, Ahmed, Mohammad, Randall, Rebecca, Chowdhury, Hasnin M., Snape, Katie M., Bradshaw, Teisha Y., Southgate, Laura, Lee, Grace J., Jackson, Ian, Lord, Graham M., Gibbs, Simon J. R., Wilkins, Martin R., Ohta-Ogo, Keiko, Nakamura, Kazufumi, Girerd, Barbara, Coulet, Florence, Soubrier, Florent, Humbert, Marc, Morrell, Nicholas W., Trembath, Richard C., and Machado, Rajiv D.

Published
2011
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6. A reduction in Drp1-mediated fission compromises mitochondrial health in autosomal recessive spastic ataxia of Charlevoix Saguenay

Author

Bradshaw, Teisha Y., Romano, Lisa E.L., Duncan, Emma J., Nethisinghe, Suran, Abeti, Rosella, Michael, Gregory J., Giunti, Paola, Vermeer, Sascha, and Chapple, J. Paul

Subjects
Dynamins, Male, Articles, Fibroblasts, Mitochondrial Dynamics, GTP Phosphohydrolases, Mitochondria, Mitochondrial Proteins, Muscle Spasticity, Cell Line, Tumor, Mitochondrial Membranes, Humans, Spinocerebellar Ataxias, Female, Microtubule-Associated Proteins, Heat-Shock Proteins
Abstract

The neurodegenerative disease autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) is caused by loss of function of sacsin, a modular protein that is required for normal mitochondrial network organization. To further understand cellular consequences of loss of sacsin, we performed microarray analyses in sacsin knockdown cells and ARSACS patient fibroblasts. This identified altered transcript levels for oxidative phosphorylation and oxidative stress genes. These changes in mitochondrial gene networks were validated by quantitative reverse transcription PCR. Functional impairment of oxidative phosphorylation was then demonstrated by comparison of mitochondria bioenergetics through extracellular flux analyses. Moreover, staining with the mitochondrial-specific fluorescent probe MitoSox suggested increased levels of superoxide in patient cells with reduced levels of sacsin. Key to maintaining mitochondrial health is mitochondrial fission, which facilitates the dynamic exchange of mitochondrial components and separates damaged parts of the mitochondrial network for selective elimination by mitophagy. Fission is dependent on dynamin-related protein 1 (Drp1), which is recruited to prospective sites of division where it mediates scission. In sacsin knockdown cells and ARSACS fibroblasts, we observed a decreased incidence of mitochondrial associated Drp1 foci. This phenotype persists even when fission is induced by drug treatment. Mitochondrial-associated Drp1 foci are also smaller in sacsin knockdown cells and ARSACS fibroblasts. These data suggest a model for ARSACS where neurons with reduced levels of sacsin are compromised in their ability to recruit or retain Drp1 at the mitochondrial membrane leading to a decline in mitochondrial health, potentially through impaired mitochondrial quality control.

Published
2016

7. Oncometabolite induced primary cilia loss in pheochromocytoma

Author

O’Toole, Samuel M, primary, Watson, David S, additional, Novoselova, Tatiana V, additional, Romano, Lisa E L, additional, King, Peter J, additional, Bradshaw, Teisha Y, additional, Thompson, Clare L, additional, Knight, Martin M, additional, Sharp, Tyson V, additional, Barnes, Michael R, additional, Srirangalingam, Umasuthan, additional, Drake, William M, additional, and Chapple, J Paul, additional

Published
2019
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8. Altered organization of the intermediate filament cytoskeleton and relocalization of proteostasis modulators in cells lacking the ataxia protein sacsin

Author

Duncan, Emma J., primary, Larivière, Roxanne, additional, Bradshaw, Teisha Y., additional, Longo, Fabiana, additional, Sgarioto, Nicolas, additional, Hayes, Matthew J., additional, Romano, Lisa E.L., additional, Nethisinghe, Suran, additional, Giunti, Paola, additional, Bruntraeger, Michaela B., additional, Durham, Heather D., additional, Brais, Bernard, additional, Maltecca, Francesca, additional, Gentil, Benoit J., additional, and Chapple, J. Paul, additional

Published
2017
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9. Oncometabolite induced primary cilia loss in pheochromocytoma.

Author

O'Toole, Samuel M., Watson, David S., Novoselova, Tatiana V., Romano, Lisa E. L., King, Peter J., Bradshaw, Teisha Y., Thompson, Clare L., Knight, Martin M., Sharp, Tyson V., Barnes, Michael R., Srirangalingam, Umasuthan, Drake, William M., and Chapple, J. Paul

Subjects
CILIA & ciliary motion, PHEOCHROMOCYTOMA, ADRENAL medulla, CATECHOLAMINES, HYPOXEMIA
Abstract

Primary cilia are sensory organelles involved in regulation of cellular signaling. Cilia loss is frequently observed in tumors; yet, the responsible mechanisms and consequences for tumorigenesis remain unclear. We demonstrate that cilia structure and function is disrupted in human pheochromocytomas - endocrine tumors of the adrenal medulla. This is concomitant with transcriptional changes within cilia-mediated signaling pathways that are associated with tumorigenesis generally and pheochromocytomas specifically. Importantly, cilia loss was most dramatic in patients with germline mutations in the pseudohypoxia-linked genes SDHx and VHL. Using a pheochromocytoma cell line derived from rat, we show that hypoxia and oncometabolite-induced pseudohypoxia are key drivers of cilia loss and identify that this is dependent on activation of an Aurora-A/HDAC6 cilia resorption pathway. We also show cilia loss drives dramatic transcriptional changes associated with proliferation and tumorigenesis. Our data provide evidence for primary cilia dysfunction contributing to pathogenesis of pheochromocytoma by a hypoxic/pseudohypoxic mechanism and implicates oncometabolites as ciliary regulators. This is important as pheochromocytomas can cause mortality by mechanisms including catecholamine production and malignant transformation, while hypoxia is a general feature of solid tumors. Moreover, pseudohypoxia-induced cilia resorption can be pharmacologically inhibited, suggesting potential for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Published
2019
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10. Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension

Author

Nasim, Md Talat, Ogo, Takeshi, Ahmed, Mohammad, Randall, Rebecca, Chowdhury, Hasnin M., Snape, Katie M., Bradshaw, Teisha Y., Southgate, Laura, Lee, Grace J., Jackson, Ian, Lord, Graham M., Gibbs, J. Simon R., Wilkins, Martin R., Ohta-Ogo, Keiko, Nakamura, Kazufumi, Girerd, Barbara, Coulet, Florence, Soubrier, Florent, Humbert, Marc, Morrell, Nicholas W., Trembath, Richard C., Machado, Rajiv D., Nasim, Md Talat, Ogo, Takeshi, Ahmed, Mohammad, Randall, Rebecca, Chowdhury, Hasnin M., Snape, Katie M., Bradshaw, Teisha Y., Southgate, Laura, Lee, Grace J., Jackson, Ian, Lord, Graham M., Gibbs, J. Simon R., Wilkins, Martin R., Ohta-Ogo, Keiko, Nakamura, Kazufumi, Girerd, Barbara, Coulet, Florence, Soubrier, Florent, Humbert, Marc, Morrell, Nicholas W., Trembath, Richard C., and Machado, Rajiv D.

Abstract

Heterozygous germline mutations of BMPR2 contribute to familial clustering of pulmonary arterial hypertension (PAH). To further explore the genetic basis of PAH in isolated cases, we undertook a candidate gene analysis to identify potentially deleterious variation. Members of the bone morphogenetic protein (BMP) pathway, namely SMAD1, SMAD4, SMAD5, and SMAD9, were screened by direct sequencing for gene defects. Four variants were identified in SMADs 1, 4, and 9 among a cohort of 324 PAH cases, each not detected in a substantial control population. Of three amino acid substitutions identified, two demonstrated reduced signaling activity in vitro. A putative splice site mutation in SMAD4 resulted in moderate transcript loss due to compromised splicing efficiency. These results demonstrate the role of BMPR2 mutation in the pathogenesis of PAH and indicate that variation within the SMAD family represents an infrequent cause of the disease.

11. Gain-of-function mutations of ARHGAP31, a Cdc42/Rac1 GTPase regulator, cause syndromic cutis aplasia and limb anomalies

Author

Southgate, Laura, Machado, Rajiv D., Snape, Katie M, Primeau, Martin, Dafou, Dimitra, Ruddy, Deborah M, Branney, Peter A, Fisher, Malcolm, Lee, Grace J., Simpson, Michael A., He, Yi, Bradshaw, Teisha Y., Blaumeiser, Bettina, Winship, William S., Reardon, Willie, Maher, Eamonn R., FitzPatrick, David R., Wuyts, Wim, Zenker, Martin, Lamarche-Vane, Nathalie, Trembath, Richard C., Southgate, Laura, Machado, Rajiv D., Snape, Katie M, Primeau, Martin, Dafou, Dimitra, Ruddy, Deborah M, Branney, Peter A, Fisher, Malcolm, Lee, Grace J., Simpson, Michael A., He, Yi, Bradshaw, Teisha Y., Blaumeiser, Bettina, Winship, William S., Reardon, Willie, Maher, Eamonn R., FitzPatrick, David R., Wuyts, Wim, Zenker, Martin, Lamarche-Vane, Nathalie, and Trembath, Richard C.

Abstract

Regulation of cell proliferation and motility is essential for normal development. The Rho family of GTPases plays a critical role in the control of cell polarity and migration by effecting the cytoskeleton, membrane trafficking, and cell adhesion. We investigated a recognized developmental disorder, Adams-Oliver syndrome (AOS), characterized by the combination of aplasia cutis congenita (ACC) and terminal transverse limb defects (TTLD). Through a genome-wide linkage analysis, we detected a locus for autosomal-dominant ACC-TTLD on 3q generating a maximum LOD score of 4.93 at marker rs1464311. Candidate-gene- and exome-based sequencing led to the identification of independent premature truncating mutations in the terminal exon of the Rho GTPase-activating protein 31 gene, ARHGAP31, which encodes a Cdc42/Rac1 regulatory protein. Mutant transcripts are stable and increase ARHGAP31 activity in vitro through a gain-of-function mechanism. Constitutively active ARHGAP31 mutations result in a loss of available active Cdc42 and consequently disrupt actin cytoskeletal structures. Arhgap31 expression in the mouse is substantially restricted to the terminal limb buds and craniofacial processes during early development; these locations closely mirror the sites of impaired organogenesis that characterize this syndrome. These data identify the requirement for regulated Cdc42 and/or Rac1 signaling processes during early human development.

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