title: VCP and ATL1 regulate endoplasmic reticulum and protein synthesis for dendritic spine formation.
abstract: Imbalanced protein homeostasis, such as excessive protein synthesis and protein aggregation, is a pathogenic hallmark of a range of neurological disorders. Here, using expression of mutant proteins, a knockdown approach and disease mutation knockin mice, we show that VCP (valosin-containing protein), together with its cofactor P47 and the endoplasmic reticulum (ER) morphology regulator ATL1 (Atlastin-1), regulates tubular ER formation and influences the efficiency of protein synthesis to control dendritic spine formation in neurons. Strengthening the significance of protein synthesis in dendritic spinogenesis, the translation blocker cyclohexamide and the mTOR inhibitor rapamycin reduce dendritic spine density, while a leucine supplement that increases protein synthesis ameliorates the dendritic spine defects caused by Vcp and Atl1 deficiencies. Because VCP and ATL1 are the causative genes of several neurodegenerative and neurodevelopmental disorders, we suggest that impaired ER formation and inefficient protein synthesis are significant in the pathogenesis of multiple neurological disorders.
authors.affiliation: Molecular Cell Biology, Taiwan International Graduate Program, Institute of Molecular Biology, Academia Sinica, and Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 115, Taiwan.|Institute of Molecular Biology, Academia Sinica, 128, Academia Road Sec 2, Nankang, Taipei 115, Taiwan.
authors.forename: Yu-Tzu
authors.initials: YT
authors.lastname: Shih
authors.affiliation: Molecular Cell Biology, Taiwan International Graduate Program, Institute of Molecular Biology, Academia Sinica, and Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 115, Taiwan.|Institute of Molecular Biology, Academia Sinica, 128, Academia Road Sec 2, Nankang, Taipei 115, Taiwan.
authors.forename: Yi-Ping
authors.identifier: http://orcid.org/0000-0002-0866-6275
authors.initials: YP
authors.lastname: Hsueh
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism*; D003513:Cycloheximide / Q000494:pharmacology; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D055879:Gene Knock-In Techniques; D055785:Gene Knockdown Techniques; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007473:Ion Channels / Q000378:metabolism; D007930:Leucine / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D014176:Protein Biosynthesis / Q000187:drug effects; D011506:Proteins / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D051381:Rats; D020123:Sirolimus / Q000494:pharmacology; D052067:Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D000074405:Valosin Containing Protein; D020691:rab GTP-Binding Proteins / Q000378:metabolism
chemical_list: D000251:Adenosine Triphosphatases; D018797:Cell Cycle Proteins; D003513:Cycloheximide; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007473:Ion Channels; D007930:Leucine; D008565:Membrane Proteins; D011506:Proteins; D020123:Sirolimus; D052067:Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins; D000074405:Valosin Containing Protein; D020691:rab GTP-Binding Proteins; C498751:Nsfl1c protein, rat; C107396:Ufd1 protein, mouse; C000589974:ATL1 protein, mouse; C520736:Rab10 protein, mouse; C000614179:Vcp protein, mouse; C000614180:Vcp protein, rat