title: Rapamycin and chloroquine: the in vitro and in vivo effects of autophagy-modifying drugs show promising results in valosin containing protein multisystem proteinopathy.
abstract: Mutations in the valosin containing protein (VCP) gene cause hereditary Inclusion body myopathy (hIBM) associated with Paget disease of bone (PDB), frontotemporal dementia (FTD), more recently termed multisystem proteinopathy (MSP). Affected individuals exhibit scapular winging and die from progressive muscle weakness, and cardiac and respiratory failure, typically in their 40s to 50s. Histologically, patients show the presence of rimmed vacuoles and TAR DNA-binding protein 43 (TDP-43)-positive large ubiquitinated inclusion bodies in the muscles. We have generated a VCPR155H/+ mouse model which recapitulates the disease phenotype and impaired autophagy typically observed in patients with VCP disease. Autophagy-modifying agents, such as rapamycin and chloroquine, at pharmacological doses have previously shown to alter the autophagic flux. Herein, we report results of administration of rapamycin, a specific inhibitor of the mechanistic target of rapamycin (mTOR) signaling pathway, and chloroquine, a lysosomal inhibitor which reverses autophagy by accumulating in lysosomes, responsible for blocking autophagy in 20-month old VCPR155H/+ mice. Rapamycin-treated mice demonstrated significant improvement in muscle performance, quadriceps histological analysis, and rescue of ubiquitin, and TDP-43 pathology and defective autophagy as indicated by decreased protein expression levels of LC3-I/II, p62/SQSTM1, optineurin and inhibiting the mTORC1 substrates. Conversely, chloroquine-treated VCPR155H/+ mice revealed progressive muscle weakness, cytoplasmic accumulation of TDP-43, ubiquitin-positive inclusion bodies and increased LC3-I/II, p62/SQSTM1, and optineurin expression levels. Our in vitro patient myoblasts studies treated with rapamycin demonstrated an overall improvement in the autophagy markers. Targeting the mTOR pathway ameliorates an increasing list of disorders, and these findings suggest that VCP disease and related neurodegenerative multisystem proteinopathies can now be included as disorders that can potentially be ameliorated by rapalogs.
authors.affiliation: Department of Pediatrics, Division of Genetics and Metabolism, University of California, Irvine, California, United States of America; Sue and Bill Gross Stem Cell Center, University of California, Irvine, California, United States of America.
authors.forename: Angèle
authors.initials: A
authors.lastname: Nalbandian
authors.affiliation: Department of Pediatrics, Division of Genetics and Metabolism, University of California, Irvine, California, United States of America; Sue and Bill Gross Stem Cell Center, University of California, Irvine, California, United States of America.
authors.forename: Katrina J
authors.initials: KJ
authors.lastname: Llewellyn
authors.affiliation: Department of Pediatrics, Division of Genetics and Metabolism, University of California, Irvine, California, United States of America.
authors.forename: Christopher
authors.initials: C
authors.lastname: Nguyen
authors.affiliation: Sue and Bill Gross Stem Cell Center, University of California, Irvine, California, United States of America; Systomic Health LLC, Los Angeles, California, United States of America.
authors.forename: Puya G
authors.initials: PG
authors.lastname: Yazdi
authors.affiliation: Department of Pediatrics, Division of Genetics and Metabolism, University of California, Irvine, California, United States of America; Sue and Bill Gross Stem Cell Center, University of California, Irvine, California, United States of America.
authors.forename: Virginia E
authors.initials: VE
authors.lastname: Kimonis
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D018797:Cell Cycle Proteins; D002460:Cell Line; D002738:Chloroquine / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000378:metabolism; D057180:Frontotemporal Dementia / Q000378:metabolism / Q000473:pathology; D055879:Gene Knock-In Techniques; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D026901:Membrane Transport Proteins; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010001:Osteitis Deformans / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005136:Eye Proteins; D036341:Intercellular Signaling Peptides and Proteins; D026901:Membrane Transport Proteins; C501288:Optn protein, mouse; D010455:Peptides; D025801:Ubiquitin; C046951:valosin; D002738:Chloroquine; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus