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

Abstract

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:
Research Org.:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1340379
Report Number(s):
BNL-112563-2016-JA
Journal ID: ISSN 1553-7404
Grant/Contract Number:  
SC00112704; AC02-98CH10886
Resource Type:
Journal Article: 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
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; Drosophila; synaptic vesicle dynamics; triosephosphate isomerase; TPI deficiency

Citation Formats

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., 2016. 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. https://doi.org/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. https://doi.org/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},
url = {https://www.osti.gov/biblio/1340379}, journal = {PLoS Genetics},
issn = {1553-7404},
number = 3,
volume = 12,
place = {United States},
year = {Thu Mar 31 00:00:00 EDT 2016},
month = {Thu Mar 31 00:00:00 EDT 2016}
}

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Cited by: 20 works
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Works referenced in this record:

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Degradation of Functional Triose Phosphate Isomerase Protein Underlies sugarkill Pathology
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Amyloid-dependent triosephosphate isomerase nitrotyrosination induces glycation and tau fibrillation
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Drosophila Model of Human Inherited Triosephosphate Isomerase Deficiency Glycolytic Enzymopathy
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Hsp70- and Hsp90-mediated proteasomal degradation underlies TPIsugarkill pathogenesis in Drosophila
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Triosephosphate Isomerase Requires a Positively Charged Active Site: The Role of Lysine-12
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Hemolytic Anemia and Progressive Neurologic Impairment: Think About Triosephosphate Isomerase Deficiency
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Triosephosphate Isomerase Requires a Positively Charged Active Site: The Role of Lysine-12
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Two types of mutants affecting voltage-sensitive sodium channels in Drosophila melanogaster
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Mechanistic Logic Underlying the Axonal Transport of Cytosolic Proteins
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Crystal Structure of the K12M/G15A Triosephosphate Isomerase Double Mutant and Electrostatic Analysis of the Active Site
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Triosephosphate isomerase deficiency: New insights into an enigmatic disease
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Triosephosphate isomerase deficiency: historical perspectives and molecular aspects
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Evidence of a triosephosphate isomerase non-catalytic function crucial to behavior and longevity
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Chaperones and Proteases: Cellular Fold-Controlling Factors of Proteins in Neurodegenerative Diseases and Aging
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FM 1-43 Labeling of Synaptic Vesicle Pools at the Drosophila Neuromuscular Junction
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ADF/Cofilin Controls Synaptic Actin Dynamics and Regulates Synaptic Vesicle Mobilization and Exocytosis
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A Temperature-Sensitive Paralytic Mutant Defines a Primary Synaptic Calcium Channel in Drosophila
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N-Cofilin Can Compensate for the Loss of ADF in Excitatory Synapses
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In Vivo Evidence for Lactate as a Neuronal Energy Source
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[20] Processing of X-ray diffraction data collected in oscillation mode
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Oxidative stress and mitochondrial dysfunction in neurodegenerative diseases
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Directed, efficient, and versatile modifications of the Drosophila genome by genomic engineering
journal, May 2009


Lactate-supported synaptic function in the rat hippocampal slice preparation
journal, June 1988


Red Cell Glycolytic Enzyme Disorders Caused by Mutations: An Update
journal, June 2009


Degradation of Functional Triose Phosphate Isomerase Protein Underlies sugarkill Pathology
journal, May 2008


Electrophilic catalysis in triosephosphate isomerase: the role of histidine-95
journal, March 1991


Efficient Ends-Out Gene Targeting In Drosophila
journal, August 2008


Analysis of Mutations Affecting Sodium Channels in Drosophila
journal, December 1986


A potent small molecule inhibits polyglutamine aggregation in Huntington's disease neurons and suppresses neurodegeneration in vivo
journal, January 2005


PHENIX: a comprehensive Python-based system for macromolecular structure solution.
text, January 2010


Hereditary Hemolytic Anemia with Triosephosphate Isomerase Deficiency
journal, February 1965


wasted away, a Drosophila mutation in triosephosphate isomerase, causes paralysis, neurodegeneration, and early death
journal, September 2006


Amyloid-dependent triosephosphate isomerase nitrotyrosination induces glycation and tau fibrillation
journal, February 2009


Three hTIM Mutants that Provide New Insights on why TIM is a Dimer
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Temperature-Sensitive Mutations in Drosophila melanogaster, VII. A Mutation (parats) Causing Reversible Adult Paralysis
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N-Cofilin Can Compensate for the Loss of ADF in Excitatory Synapses
journal, October 2011


RosettaBackrub--a web server for flexible backbone protein structure modeling and design
journal, May 2010


Central Presynaptic Terminals Are Enriched in ATP but the Majority Lack Mitochondria
journal, April 2015


Triosephosphate Isomerase Deficiency: A Patient With Val231Met Mutation
journal, February 2011


Pyruvate Kinase Triggers a Metabolic Feedback Loop that Controls Redox Metabolism in Respiring Cells
journal, September 2011


Drosophila Larval NMJ Dissection
journal, January 2009


A mutation in Drosophila Aldolase Causes Temperature-Sensitive Paralysis, Shortened Lifespan, and Neurodegeneration
journal, August 2012


Triosephosphate isomerase deficiency: Facts and doubts
journal, December 2006


FM 1-43 Labeling of Synaptic Vesicle Pools at the Drosophila Neuromuscular Junction
book, January 2008


A Drosophila NSF mutant
journal, July 1995


Drosophila twinfilin is required for cell migration and synaptic endocytosis
journal, April 2010


A Drosophila mutant with a temperature-sensitive block in nerve conduction.
journal, August 1978


Hsp70- and Hsp90-mediated proteasomal degradation underlies TPIsugarkill pathogenesis in Drosophila
journal, December 2010


Triosephosphate isomerase: a highly evolved biocatalyst
journal, August 2010


Drosophila Model of Human Inherited Triosephosphate Isomerase Deficiency Glycolytic Enzymopathy
journal, September 2006


Triosephosphate isomerase deficiency: historical perspectives and molecular aspects
journal, March 2000


The crystal structure of the “open” and the “closed” conformation of the flexible loop of trypanosomal triosephosphate isomerase
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Increased formation of methylglyoxal and protein glycation, oxidation and nitrosation in triosephosphate isomerase deficiency
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The Drosophila Wnt, Wingless, Provides an Essential Signal for Pre- and Postsynaptic Differentiation
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Oxidative stress and mitochondrial dysfunction in neurodegenerative diseases
journal, April 2007


Triosephosphate isomerase I170V alters catalytic site, enhances stability and induces pathology in a Drosophila model of TPI deficiency
journal, January 2015


Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases
journal, October 2006


Mechanistic Logic Underlying the Axonal Transport of Cytosolic Proteins
journal, May 2011


Directed, efficient, and versatile modifications of the Drosophila genome by genomic engineering
journal, May 2009


Activity-Driven Local ATP Synthesis Is Required for Synaptic Function
journal, February 2014


Central Presynaptic Terminals Are Enriched in ATP but the Majority Lack Mitochondria
journal, April 2015


Chronic axonal neuropathy with triosephosphate isomerase deficiency
journal, February 2004


Triosephosphate isomerase deficiency: New insights into an enigmatic disease
journal, December 2009


In vitro and in silico trichomonacidal activity of 2,8-bis(trifluoromethyl) quinoline analogs against Trichomonas vaginalis
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Synaptic Vesicle Endocytosis
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Early mitochondrial dysfunction leads to altered redox chemistry underlying pathogenesis of TPI deficiency
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Interaction of Cofilin with Triose-phosphate Isomerase Contributes Glycolytic Fuel for Na,K-ATPase via Rho-mediated Signaling Pathway
journal, September 2002


A Drosophila NSF mutant
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A mutation in Drosophila Aldolase Causes Temperature-Sensitive Paralysis, Shortened Lifespan, and Neurodegeneration
journal, August 2012


Evidence of a triosephosphate isomerase non-catalytic function crucial to behavior and longevity
journal, May 2013


Triosephosphate Isomerase Deficiency: A Patient With Val231Met Mutation
journal, February 2011


The Role of Mitochondrially Derived ATP in Synaptic Vesicle Recycling
journal, September 2015


Temperature-Sensitive Paralytic Mutants Are Enriched For Those Causing Neurodegeneration in Drosophila
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Low catalytic activity is insufficient to induce disease pathology in triosephosphate isomerase deficiency.
text, January 2020


Medical and Veterinary Importance of the Moonlighting Functions of Triosephosphate Isomerase
journal, February 2019


Bone marrow transplantation corrects haemolytic anaemia in a novel ENU mutagenesis mouse model of TPI deficiency
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Low catalytic activity is insufficient to induce disease pathology in triosephosphate isomerase deficiency
journal, June 2019


Low catalytic activity is insufficient to induce disease pathology in triosephosphate isomerase deficiency.
text, January 2020