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.
Highlights
Imbalanced protein homeostasis, such as excessive protein synthesis and protein aggregation, is a pathogenic hallmark of a range of neurological disorders
Our study suggests that the VCP-P47 complex acts with an endoplasmic reticulum (ER) regulator, ATL1, to regulate ER morphology and protein synthesis, which are critical for dendritic spinogenesis
We investigated whether P47 is involved in dendritic spinogenesis
Summary
Imbalanced protein homeostasis, such as excessive protein synthesis and protein aggregation, is a pathogenic hallmark of a range of neurological disorders. 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. VCP, known as P97, is one of the genes controlling protein homeostasis and is associated with neurological disorders. Vcp encodes a hexameric AAA þ ATPase that functions as a chaperone to control diverse cellular processes, including endoplasmic reticulum (ER)-associated protein degradation (ERAD)[6,7], the ubiquitin–proteasome system (UPS)[8,9], ER and Golgi morphogenesis[10,11,12,13,14,15,16,17] and others[9,18,19]. Our study suggests that the VCP-P47 complex acts with an ER regulator, ATL1, to regulate ER morphology and protein synthesis, which are critical for dendritic spinogenesis
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