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

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. Also, 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.
Authors:
 [1] ;  [1] ;  [1] ;  [2] ;  [1] ;  [1] ;  [3] ;  [4] ;  [2] ;  [1]
  1. Univ. of Pittsburgh, PA (United States). Department of Pharmacology & Chemical Biology; University of Pittsburgh School of Medicine, Pittsburgh, PA (United States). The Pittsburgh Institute for Neurodegenerative Diseases (PIND)
  2. Univ. of Pittsburgh, PA (United States). Department of Biological Sciences
  3. Brookhaven National Lab. (BNL), Upton, NY (United States). Energy Sciences Directorate/Photon Science Division
  4. Univ. of Pittsburgh, PA (United States). Department of Pharmacology & Chemical Biology
Publication Date:
Report Number(s):
BNL-112563-2016-JA
Journal ID: ISSN 1553-7404
Grant/Contract Number:
SC00112704; AC02-98CH10886
Type:
Accepted Manuscript
Journal Name:
PLoS Genetics
Additional Journal Information:
Journal Volume: 12; Journal Issue: 3; Journal ID: ISSN 1553-7404
Publisher:
Public Library of Science
Research Org:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; Drosophila; synaptic vesicle dynamics; triosephosphate isomerase; TPI deficiency
OSTI Identifier:
1340379

Roland, Bartholomew P., Zeccola, Alison M., Larsen, Samantha B., Amrich, Christopher G., Talsma, Aaron D., Stuchul, Kimberly A., Heroux, Annie, Levitan, Edwin S., VanDemark, Andrew P., and Palladino, Michael J.. Structural and Genetic Studies Demonstrate Neurologic Dysfunction in Triosephosphate Isomerase Deficiency Is Associated with Impaired Synaptic Vesicle Dynamics. United States: N. p., Web. doi:10.1371/journal.pgen.1005941.
Roland, Bartholomew P., Zeccola, Alison M., Larsen, Samantha B., Amrich, Christopher G., Talsma, Aaron D., Stuchul, Kimberly A., Heroux, Annie, Levitan, Edwin S., VanDemark, Andrew P., & Palladino, Michael J.. Structural and Genetic Studies Demonstrate Neurologic Dysfunction in Triosephosphate Isomerase Deficiency Is Associated with Impaired Synaptic Vesicle Dynamics. United States. doi:10.1371/journal.pgen.1005941.
Roland, Bartholomew P., Zeccola, Alison M., Larsen, Samantha B., Amrich, Christopher G., Talsma, Aaron D., Stuchul, Kimberly A., Heroux, Annie, Levitan, Edwin S., VanDemark, Andrew P., and Palladino, Michael J.. 2016. "Structural and Genetic Studies Demonstrate Neurologic Dysfunction in Triosephosphate Isomerase Deficiency Is Associated with Impaired Synaptic Vesicle Dynamics". United States. doi:10.1371/journal.pgen.1005941. https://www.osti.gov/servlets/purl/1340379.
@article{osti_1340379,
title = {Structural and Genetic Studies Demonstrate Neurologic Dysfunction in Triosephosphate Isomerase Deficiency Is Associated with Impaired Synaptic Vesicle Dynamics},
author = {Roland, Bartholomew P. and Zeccola, Alison M. and Larsen, Samantha B. and Amrich, Christopher G. and Talsma, Aaron D. and Stuchul, Kimberly A. and Heroux, Annie and Levitan, Edwin S. and VanDemark, Andrew P. and Palladino, Michael J.},
abstractNote = {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. Also, 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.},
doi = {10.1371/journal.pgen.1005941},
journal = {PLoS Genetics},
number = 3,
volume = 12,
place = {United States},
year = {2016},
month = {3}
}