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4. Autoregulation of Parkin activity through its ubiquitin-like domain

Author

Chaugule, Viduth K, Burchell, Lynn, Barber, Kathryn R, Sidhu, Ateesh, Leslie, Simon J, Shaw, Gary S, and Walden, Helen

Subjects
Have You Seen...?, Sequence Homology, Amino Acid, Protein Conformation, Ubiquitin, Ubiquitin-Protein Ligases, Molecular Sequence Data, Parkinson Disease, Article, Gene Expression Regulation, Enzymologic, Peptide Fragments, nervous system diseases, Mutation, Homeostasis, Humans, Amino Acid Sequence
Abstract

Parkin is an E3-ubiquitin ligase belonging to the RBR (RING-InBetweenRING-RING family), and is involved in the neurodegenerative disorder Parkinson's disease. Autosomal recessive juvenile Parkinsonism, which is one of the most common familial forms of the disease, is directly linked to mutations in the parkin gene. However, the molecular mechanisms of Parkin dysfunction in the disease state remain to be established. We now demonstrate that the ubiquitin-like domain of Parkin functions to inhibit its autoubiquitination. Moreover pathogenic Parkin mutations disrupt this autoinhibition, resulting in a constitutively active molecule. In addition, we show that the mechanism of autoregulation involves ubiquitin binding by a C-terminal region of Parkin. Our observations provide important molecular insights into the underlying basis of Parkinson's disease, and in the regulation of RBR E3-ligase activity.

Published
2011

6. Minimal impact of age and housing temperature on the metabolic phenotype of Acc2-/- mice.

Author

Brandon, Amanda E., Stuart, Ella, Leslie, Simon J., Hoehn, Kyle L., James, David E., Kraegen, Edward W., Turner, Nigel, and Cooney, Gregory J.

Subjects
PHENOTYPES, FATTY acid oxidation, ALLOSTERIC regulation, MALONYL-coenzyme A, ENZYME inhibitors, LABORATORY mice
Abstract

An important regulator of fatty acid oxidation (FAO) is the allosteric inhibition of CPT-1 by malonyl-CoA produced by the enzyme acetyl-CoA carboxylase 2 (ACC2). Initial studies suggested that deletion of Acc2 (Acacb) increased fat oxidation and reduced adipose tissue mass but in an independently generated strain of Acc2 knockout mice we observed increased whole-body and skeletal muscle FAO and a compensatory increase in muscle glycogen stores without changes in glucose tolerance, energy expenditure or fat mass in young mice (12-16 weeks). The aim of the present study was to determine whether there was any effect of age or housing at thermoneutrality (29°C; which reduces total energy expenditure) on the phenotype of Acc2 knockout mice. At 42-54 weeks of age, male WT and Acc2-/- mice had similar body weight, fat mass, muscle triglyceride content and glucose tolerance. Consistent with younger Acc2-/- mice, aged Acc2-/- mice showed increased whole-body FAO (24 h average respiratory exchange ratioZ0.95±0.02 and 0.92±0.02 for WT and Acc2-/- mice respectively, P<0.05) and skeletal muscle glycogen content (C60%, P<0.05) without any detectable change in whole-body energy expenditure. Hyperinsulinaemic- euglycaemic clamp studies revealed no difference in insulin action between groups with similar glucose infusion rates and tissue glucose uptake. Housing Acc2-/- mice at 29°C did not alter body composition, glucose tolerance or the effects of fat feeding compared with WT mice. These results confirm that manipulation of Acc2 may alter FAO in mice, but this has little impact on body composition or insulin action. [ABSTRACT FROM AUTHOR]

Published
2016
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9. Minimal impact of age and housing temperature on the metabolic phenotype of Acc2-/- mice.

Author

Brandon AE, Stuart E, Leslie SJ, Hoehn KL, James DE, Kraegen EW, Turner N, and Cooney GJ

Subjects
Acetyl-CoA Carboxylase deficiency, Animals, Body Composition, Body Weight, Energy Metabolism, Fatty Acids metabolism, Glucose Clamp Technique, Glucose Tolerance Test, Glycogen analysis, Insulin blood, Male, Mice, Mice, Knockout, Muscle, Skeletal chemistry, Muscle, Skeletal metabolism, Oxidation-Reduction, Phenotype, Triglycerides analysis, Acetyl-CoA Carboxylase physiology, Aging physiology, Housing, Animal, Temperature
Abstract

An important regulator of fatty acid oxidation (FAO) is the allosteric inhibition of CPT-1 by malonyl-CoA produced by the enzyme acetyl-CoA carboxylase 2 (ACC2). Initial studies suggested that deletion of Acc2 (Acacb) increased fat oxidation and reduced adipose tissue mass but in an independently generated strain of Acc2 knockout mice we observed increased whole-body and skeletal muscle FAO and a compensatory increase in muscle glycogen stores without changes in glucose tolerance, energy expenditure or fat mass in young mice (12-16 weeks). The aim of the present study was to determine whether there was any effect of age or housing at thermoneutrality (29 °C; which reduces total energy expenditure) on the phenotype of Acc2 knockout mice. At 42-54 weeks of age, male WT and Acc2(-/-) mice had similar body weight, fat mass, muscle triglyceride content and glucose tolerance. Consistent with younger Acc2(-/-) mice, aged Acc2(-/-) mice showed increased whole-body FAO (24 h average respiratory exchange ratio=0.95±0.02 and 0.92±0.02 for WT and Acc2(-/-) mice respectively, P<0.05) and skeletal muscle glycogen content (+60%, P<0.05) without any detectable change in whole-body energy expenditure. Hyperinsulinaemic-euglycaemic clamp studies revealed no difference in insulin action between groups with similar glucose infusion rates and tissue glucose uptake. Housing Acc2(-/-) mice at 29 °C did not alter body composition, glucose tolerance or the effects of fat feeding compared with WT mice. These results confirm that manipulation of Acc2 may alter FAO in mice, but this has little impact on body composition or insulin action., (© 2016 Society for Endocrinology.)

Published
2016
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