المؤلفون: Finkbeiner, Steven, Barmada, SJ, Serio, A, Arjun, A, Bilican, B, Daub, A, Ando, DM, Tsvetkov, A, Pleiss, M, Li, X, Peisach, D

الوصف: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have distinct clinical features but a common pathology-cytoplasmic inclusions rich in transactive response element DNA-binding protein of 43 kDa (TDP43). Rare TDP43 mutations cause ALS o

URL الوصول: https://escholarship.org/uc/item/0q3836sf

المؤلفون: Barmada, SJ, Serio, A, Arjun, A, Bilican, B, Daub, A, Ando, DM, Tsvetkov, A, Pleiss, M, Li, X, Peisach, D, Shaw, C, Chandran, S, Finkbeiner, S

المصدر: Nature Chemical Biology. 10(8)

مصطلحات موضوعية: Biochemistry & Molecular Biology, Medicinal and Biomolecular Chemistry, Biochemistry and Cell Biology

الوصف: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have distinct clinical features but a common pathology - cytoplasmic inclusions rich in transactive response element DNA-binding protein of 43 kDa (TDP43). Rare TDP43 mutations cause ALS or FTD, but abnormal TDP43 levels and localization may cause disease even if TDP43 lacks a mutation. Here we show that individual neurons vary in their ability to clear TDP43 and are exquisitely sensitive to TDP43 levels. To measure TDP43 clearance, we developed and validated a single-cell optical method that overcomes the confounding effects of aggregation and toxicity and discovered that pathogenic mutations shorten TDP43 half-life. New compounds that stimulate autophagy improved TDP43 clearance and localization and enhanced survival in primary murine neurons and in human stem cell-derived neurons and astrocytes harboring mutant TDP43. These findings indicate that the levels and localization of TDP43 critically determine neurotoxicity and show that autophagy induction mitigates neurodegeneration by acting directly on TDP43 clearance. © 2014 Nature America, Inc. All rights reserved.

وصف الملف: application/pdf

URL الوصول: https://escholarship.org/uc/item/6z83h67w

لا يتم عرض هذه النتيجة على الضيوف.
تسجيل الدخول للوصول الكامل.

لا يتم عرض هذه النتيجة على الضيوف.
تسجيل الدخول للوصول الكامل.

لا يتم عرض هذه النتيجة على الضيوف.
تسجيل الدخول للوصول الكامل.

لا يتم عرض هذه النتيجة على الضيوف.
تسجيل الدخول للوصول الكامل.

لا يتم عرض هذه النتيجة على الضيوف.
تسجيل الدخول للوصول الكامل.

المؤلفون: Sugio, S., Kashima, A., Kishimoto, K., Peisach, D., Petsko, G. A., Ringe, D., Yoshimura, T., Esaki, N.

المصدر: Protein Engineering; Aug98, Vol. 11 Issue 8, p613, 8p

لا يتم عرض هذه النتيجة على الضيوف.
تسجيل الدخول للوصول الكامل.

المؤلفون: Sugio, S, Kashima, A, Kishimoto, K, Peisach, D, Petsko, GA, Ringe, D, Yoshimura, T, Esaki, N

المصدر: Protein Engineering Design and Selection; August 1998, Vol. 11 Issue: 8 p613-619, 7p

مستخلص: The leucine-to-alanine mutation at residue 201 of D-amino acid aminotransferase provides a unique enzyme which gradually loses its activity while catalyzing the normal transamination; the co-enzyme form is converted from pyridoxal 5'-phosphate to pyridoxamine 5'-phosphate upon the inactivation [Kishimoto,K., Yoshimura,T., Esaki,N., Sugio,S., Manning,J.M. and Soda,K. (1995) J. Biochem., 117, 691-696]. Crystal structures of both co-enzyme forms of the mutant enzyme have been determined at 2.0 bi resolution: they are virtually identical, and are quite similar to that of the wild-type enzyme. Significant differences in both forms of the mutant are localized only on the bound co-enzyme, the side chains of Lys145 and Tyr31, and a water molecule sitting on the putative substrate binding site. Detailed comparisons of the structures of the mutant, together with that of the pyridoxamine-5'-phosphate form of the wild-type enzyme, imply that Leu201 would play a crucial role in the transamination reaction by keeping the pyridoxyl ring in the proper location without disturbing its oscillating motion, although the residue seems to not be especially important for the structural integrity of the enzyme.Keywords:crystal structure/D-amino acid aminotransferase/pyridoxal-5'-phosphate/reaction mechanism/site-directed mutagenesis