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PLoS Genet. 2016 Mar 31;12(3):e1005941. doi: 10.1371/journal.pgen.1005941. eCollection 2016 Mar.

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

Author information

1
Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
2
The Pittsburgh Institute for Neurodegenerative Diseases (PIND), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
3
Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
4
Energy Sciences Directorate/Photon Science Division, Brookhaven National Laboratory, Upton, New York, United States of America.

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. 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.

PMID:
27031109
PMCID:
PMC4816394
DOI:
10.1371/journal.pgen.1005941
[Indexed for MEDLINE]
Free PMC Article

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