AAV9-TAZ Gene Replacement Ameliorates Cardiac TMT Proteomic Profiles in a Mouse Model of Barth Syndrome

Molecular Therapy. Methods & Clinical Development
Silveli Suzuki-HatanoChristina A Pacak

Abstract

Barth syndrome (BTHS) is a rare mitochondrial disease that causes severe cardiomyopathy and has no disease-modifying therapy. It is caused by recessive mutations in the gene tafazzin (TAZ), which encodes tafazzin-an acyltransferase that remodels the inner mitochondrial membrane lipid cardiolipin. To identify novel mechanistic pathways involved in BTHS and evaluate the effects of gene therapy on proteomic profiles, we performed a multiplex tandem mass tagging (TMT) quantitative proteomics analysis to compare protein expression profiles from heart lysates isolated from BTHS, healthy wild-type (WT), and BTHS treated with adeno-associated virus serotype 9 (AAV9)-TAZ gene replacement as neonates or adults. 197 proteins with ≥2 unique peptides were identified. Of these, 91 proteins were significantly differentially expressed in BTHS compared to WT controls. Cause-effect relationships between tafazzin deficiency and altered protein profiles were confirmed through demonstrated significant improvements in expression levels following administration of AAV9-TAZ. The importance of TMEM65 in Cx43 localization to cardiac intercalated discs was revealed as a novel consequence of tafazzin deficiency that was improved following gene therapy. Th...Continue Reading

Citations

Jul 25, 2019·International Journal of Molecular Sciences·Silveli Suzuki-HatanoChristina A Pacak
Oct 12, 2019·American Journal of Physiology. Heart and Circulatory Physiology·Mindong RenColin K L Phoon
Nov 11, 2019·Journal of Nuclear Cardiology : Official Publication of the American Society of Nuclear Cardiology·William Todd CadeLinda R Peterson
May 28, 2020·Journal of Developmental Biology·Michael T Chin, Simon J Conway

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Methods Mentioned

BETA
electrophoresis
PCR
proteomics profiling
NMR
transgenic
genotyping
Affinity Purification
Protein Assay

Software Mentioned

GraphPad Prism
SEQUEST
Search Tool for the Retrieval of Interacting Genes / Proteins ...
TMT
Protein Analysis trough Evolutionary Relationships ( PANTHER )
Proteome Discoverer
PANTHER
STRING

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