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Structural and Genetic Studies Demonstrate Neurologic Dysfunction in Triosephosphate Isomerase Deficiency Is Associated with Impaired Synaptic Vesicle Dynamics

Roland, BP and Zeccola, AM and Larsen, SB and Amrich, CG and Talsma, AD and Stuchul, KA and Heroux, A and Levitan, ES and VanDemark, AP and Palladino, MJ (2016) Structural and Genetic Studies Demonstrate Neurologic Dysfunction in Triosephosphate Isomerase Deficiency Is Associated with Impaired Synaptic Vesicle Dynamics. PLoS Genetics, 12 (3). ISSN 1553-7390

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Abstract

© 2016, Public Library of Science. All Rights Reserved. Triosephosphate isomerase (TPI) deficiency is a poorly understood disease characterized by hemolytic anemia, cardiomyopathy, neurologic dysfunction, and early death. TPI deficiency is one of a group of diseases known as glycolytic enzymopathies, but is unique for its severe patient neuropathology and early mortality. The disease is caused by missense mutations and dysfunction in the glycolytic enzyme, TPI. Previous studies have detailed structural and catalytic changes elicited by disease-associated TPI substitutions, and samples of patient erythrocytes have yielded insight into patient hemolytic anemia; however, the neuropathophysiology of this disease remains a mystery. This study combines structural, biochemical, and genetic approaches to demonstrate that perturbations of the TPI dimer interface are sufficient to elicit TPI deficiency neuropathogenesis. The present study demonstrates that neurologic dysfunction resulting from TPI deficiency is characterized by synaptic vesicle dysfunction, and can be attenuated with catalytically inactive TPI. Collectively, our findings are the first to identify, to our knowledge, a functional synaptic defect in TPI deficiency derived from molecular changes in the TPI dimer interface.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Roland, BP
Zeccola, AM
Larsen, SB
Amrich, CG
Talsma, AD
Stuchul, KAkas433@pitt.eduKAS433
Heroux, A
Levitan, ESelevitan@pitt.eduELEVITAN
VanDemark, APandyv@pitt.eduANDYV0000-0003-3424-4831
Palladino, MJmjp44@pitt.eduMJP44
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorPallanck, Leo J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 1 March 2016
Date Type: Publication
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title: PLoS Genetics
Volume: 12
Number: 3
DOI or Unique Handle: 10.1371/journal.pgen.1005941
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Biological Sciences
School of Medicine > Pharmacology and Chemical Biology
Refereed: Yes
ISSN: 1553-7390
Date Deposited: 23 Aug 2016 13:41
Last Modified: 19 Jun 2018 23:55
URI: http://d-scholarship.pitt.edu/id/eprint/28517

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