Repression of phosphatidylinositol transfer protein α ameliorates the pathology of Duchenne muscular dystrophy.

Autor:	Vieira NM; Centro do Genoma Humano e Células-tronco, Instituto de Biociências, Universidade de São Paulo, São Paulo 05508-090, Brazil.; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115.; Departments of Pediatrics and Genetics, Harvard Medical School, Boston, MA 02115., Spinazzola JM; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115.; Departments of Pediatrics and Genetics, Harvard Medical School, Boston, MA 02115., Alexander MS; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115.; Departments of Pediatrics and Genetics, Harvard Medical School, Boston, MA 02115.; The Stem Cell Program, Boston Children's Hospital, Boston, MA 02115., Moreira YB; Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo 05508-900, Brazil., Kawahara G; Department of Pathophysiology, Tokyo Medical University, Tokyo 160-0022, Japan., Gibbs DE; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115., Mead LC; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115., Verjovski-Almeida S; Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo 05508-900, Brazil.; Laboratory of Gene Expression in Eukaryotes, Instituto Butantan, São Paulo 05503-900, Brazil., Zatz M; Centro do Genoma Humano e Células-tronco, Instituto de Biociências, Universidade de São Paulo, São Paulo 05508-090, Brazil., Kunkel LM; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115; kunkel@enders.tch.harvard.edu.; Departments of Pediatrics and Genetics, Harvard Medical School, Boston, MA 02115.; The Stem Cell Program, Boston Children's Hospital, Boston, MA 02115.; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138.; The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2017 Jun 06; Vol. 114 (23), pp. 6080-6085. Date of Electronic Publication: 2017 May 22.
DOI:	10.1073/pnas.1703556114
Abstrakt:	Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease caused by X-linked inherited mutations in the DYSTROPHIN ( DMD ) gene. Absence of dystrophin protein from the sarcolemma causes severe muscle degeneration, fibrosis, and inflammation, ultimately leading to cardiorespiratory failure and premature death. Although there are several promising strategies under investigation to restore dystrophin protein expression, there is currently no cure for DMD, and identification of genetic modifiers as potential targets represents an alternative therapeutic strategy. In a Brazilian golden retriever muscular dystrophy (GRMD) dog colony, two related dogs demonstrated strikingly mild dystrophic phenotypes compared with those typically observed in severely affected GRMD dogs despite lacking dystrophin. Microarray analysis of these "escaper" dogs revealed reduced expression of phosphatidylinositol transfer protein-α ( PITPNA ) in escaper versus severely affected GRMD dogs. Based on these findings, we decided to pursue investigation of modulation of PITPNA expression on dystrophic pathology in GRMD dogs, dystrophin-deficient sapje zebrafish, and human DMD myogenic cells. In GRMD dogs, decreased expression of Pitpna was associated with increased phosphorylated Akt (pAkt) expression and decreased PTEN levels. PITPNA knockdown by injection of morpholino oligonucleotides in sapje zebrafish also increased pAkt, rescued the abnormal muscle phenotype, and improved long-term sapje mutant survival. In DMD myotubes, PITPNA knockdown by lentiviral shRNA increased pAkt and increased myoblast fusion index. Overall, our findings suggest PIPTNA as a disease modifier that accords benefits to the abnormal signaling, morphology, and function of dystrophic skeletal muscle, and may be a target for DMD and related neuromuscular diseases. Competing Interests: Conflict of interest statement: L.M.K. is a consultant for Pfizer, Inc., Summit Corporation PLC, and Sarepta Therapeutics for muscle disease drug therapies.
Databáze:	MEDLINE
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