Myogenic differentiation of VCP disease-induced pluripotent stem cells: A novel platform for drug discovery

Valosin Containing Protein (VCP) disease is an autosomal dominant multisystem proteinopathy caused by mutations in the VCP gene, and is primarily associated with progressive muscle weakness, including atrophy of the pelvic and shoulder girdle muscles. Currently, no treatments are available and cardi...

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Veröffentlicht in:PloS one 2017-06, Vol.12 (6), p.e0176919
Hauptverfasser: Llewellyn, Katrina J, Nalbandian, Angèle, Weiss, Lan N, Chang, Isabela, Yu, Howard, Khatib, Bibo, Tan, Baichang, Scarfone, Vanessa, Kimonis, Virginia E
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container_issue 6
container_start_page e0176919
container_title PloS one
container_volume 12
creator Llewellyn, Katrina J
Nalbandian, Angèle
Weiss, Lan N
Chang, Isabela
Yu, Howard
Khatib, Bibo
Tan, Baichang
Scarfone, Vanessa
Kimonis, Virginia E
description Valosin Containing Protein (VCP) disease is an autosomal dominant multisystem proteinopathy caused by mutations in the VCP gene, and is primarily associated with progressive muscle weakness, including atrophy of the pelvic and shoulder girdle muscles. Currently, no treatments are available and cardiac and respiratory failures can lead to mortality at an early age. VCP is an AAA ATPase multifunction complex protein and mutations in the VCP gene resulting in disrupted autophagic clearance. Due to the rarity of the disease, the myopathic nature of the disorder, ethical and practical considerations, VCP disease muscle biopsies are difficult to obtain. Thus, disease-specific human induced pluripotent stem cells (hiPSCs) now provide a valuable resource for the research owing to their renewable and pluripotent nature. In the present study, we report the differentiation and characterization of a VCP disease-specific hiPSCs into precursors expressing myogenic markers including desmin, myogenic factor 5 (MYF5), myosin and heavy chain 2 (MYH2). VCP disease phenotype is characterized by high expression of TAR DNA Binding Protein-43 (TDP-43), ubiquitin (Ub), Light Chain 3-I/II protein (LC3-I/II), and p62/SQSTM1 (p62) protein indicating disruption of the autophagy cascade. Treatment of hiPSC precursors with autophagy stimulators Rapamycin, Perifosine, or AT101 showed reduction in VCP pathology markers TDP-43, LC3-I/II and p62/SQSTM1. Conversely, autophagy inhibitors chloroquine had no beneficial effect, and Spautin-1 or MHY1485 had modest effects. Our results illustrate that hiPSC technology provide a useful platform for a rapid drug discovery and hence constitutes a bridge between clinical and bench research in VCP and related diseases.
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VCP disease phenotype is characterized by high expression of TAR DNA Binding Protein-43 (TDP-43), ubiquitin (Ub), Light Chain 3-I/II protein (LC3-I/II), and p62/SQSTM1 (p62) protein indicating disruption of the autophagy cascade. Treatment of hiPSC precursors with autophagy stimulators Rapamycin, Perifosine, or AT101 showed reduction in VCP pathology markers TDP-43, LC3-I/II and p62/SQSTM1. Conversely, autophagy inhibitors chloroquine had no beneficial effect, and Spautin-1 or MHY1485 had modest effects. 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Llewellyn, Katrina J</au><au>Nalbandian, Angèle</au><au>Weiss, Lan N</au><au>Chang, Isabela</au><au>Yu, Howard</au><au>Khatib, Bibo</au><au>Tan, Baichang</au><au>Scarfone, Vanessa</au><au>Kimonis, Virginia E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Myogenic differentiation of VCP disease-induced pluripotent stem cells: A novel platform for drug discovery</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2017-06-02</date><risdate>2017</risdate><volume>12</volume><issue>6</issue><spage>e0176919</spage><pages>e0176919-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Valosin Containing Protein (VCP) disease is an autosomal dominant multisystem proteinopathy caused by mutations in the VCP gene, and is primarily associated with progressive muscle weakness, including atrophy of the pelvic and shoulder girdle muscles. Currently, no treatments are available and cardiac and respiratory failures can lead to mortality at an early age. VCP is an AAA ATPase multifunction complex protein and mutations in the VCP gene resulting in disrupted autophagic clearance. Due to the rarity of the disease, the myopathic nature of the disorder, ethical and practical considerations, VCP disease muscle biopsies are difficult to obtain. Thus, disease-specific human induced pluripotent stem cells (hiPSCs) now provide a valuable resource for the research owing to their renewable and pluripotent nature. In the present study, we report the differentiation and characterization of a VCP disease-specific hiPSCs into precursors expressing myogenic markers including desmin, myogenic factor 5 (MYF5), myosin and heavy chain 2 (MYH2). VCP disease phenotype is characterized by high expression of TAR DNA Binding Protein-43 (TDP-43), ubiquitin (Ub), Light Chain 3-I/II protein (LC3-I/II), and p62/SQSTM1 (p62) protein indicating disruption of the autophagy cascade. Treatment of hiPSC precursors with autophagy stimulators Rapamycin, Perifosine, or AT101 showed reduction in VCP pathology markers TDP-43, LC3-I/II and p62/SQSTM1. Conversely, autophagy inhibitors chloroquine had no beneficial effect, and Spautin-1 or MHY1485 had modest effects. Our results illustrate that hiPSC technology provide a useful platform for a rapid drug discovery and hence constitutes a bridge between clinical and bench research in VCP and related diseases.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28575052</pmid><doi>10.1371/journal.pone.0176919</doi><oa>free_for_read</oa></addata></record>
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subjects Adenosine triphosphatase
Adenosine Triphosphatases - genetics
Age
Alzheimer's disease
Amyotrophic lateral sclerosis
Analysis
Animals
Atrophy
Autophagy
Binding
Biology and Life Sciences
Biomarkers
Bladder cancer
Cardiomyopathy
Case-Control Studies
Cell Cycle Proteins - genetics
Cell death
Cell Differentiation
Cells, Cultured
Chloroquine
Dementia
Deoxyribonucleic acid
Desmin
Differentiation
Diseases
Disruption
DNA
Drug Discovery
Ethics
Failure
Gene expression
Heart diseases
Humans
Inhibitors
Medical research
Medicine
Medicine and Health Sciences
Mice
Mortality
Muscle, Skeletal - pathology
Muscles
Muscular Diseases - genetics
Muscular Diseases - pathology
Mutation
Myosin
Pathology
Patients
Pediatrics
Phagocytosis
Pluripotency
Pluripotent Stem Cells - cytology
Proteins
Rapamycin
Shoulder
Stem cells
Stimulators
Technology
Therapeutics
Ubiquitin
Valosin Containing Protein
title Myogenic differentiation of VCP disease-induced pluripotent stem cells: A novel platform for drug discovery
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