RRC ID 36290
著者 Roland BP, Zeccola AM, Larsen SB, Amrich CG, Talsma AD, Stuchul KA, Heroux A, Levitan ES, VanDemark AP, Palladino MJ.
タイトル Structural and Genetic Studies Demonstrate Neurologic Dysfunction in Triosephosphate Isomerase Deficiency Is Associated with Impaired Synaptic Vesicle Dynamics.
ジャーナル PLoS Genet
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.
巻・号 12(3)
ページ e1005941
公開日 2016-3-1
DOI 10.1371/journal.pgen.1005941
PII PGENETICS-D-15-02198
PMID 27031109
PMC PMC4816394
MeSH Anemia, Hemolytic, Congenital Nonspherocytic / genetics* Anemia, Hemolytic, Congenital Nonspherocytic / pathology Animals Behavior, Animal Carbohydrate Metabolism, Inborn Errors / genetics* Carbohydrate Metabolism, Inborn Errors / pathology Crystallography, X-Ray Dimerization Drosophila melanogaster / genetics* Humans Mutation, Missense Nervous System Diseases / genetics* Nervous System Diseases / pathology Protein Conformation Synaptic Vesicles / genetics* Synaptic Vesicles / pathology Triose-Phosphate Isomerase / chemistry Triose-Phosphate Isomerase / deficiency* Triose-Phosphate Isomerase / genetics* Triose-Phosphate Isomerase / metabolism
IF 5.175
引用数 9
WOS 分野 GENETICS & HEREDITY
リソース情報
ショウジョウバエ DGRC#108492