title: TRIAD3/RNF216 mutations associated with Gordon Holmes syndrome lead to synaptic and cognitive impairments via Arc misregulation.
abstract: Multiple loss-of-function mutations in TRIAD3 (a.k.a. RNF216) have recently been identified in patients suffering from Gordon Holmes syndrome (GHS), characterized by cognitive decline, dementia, and movement disorders. TRIAD3A is an E3 ubiquitin ligase that recognizes and facilitates the ubiquitination of its target for degradation by the ubiquitin-proteasome system (UPS). Here, we demonstrate that two of these missense substitutions in TRIAD3 (R660C and R694C) could not regulate the degradation of their neuronal target, activity-regulated cytoskeletal-associated protein (Arc/Arg 3.1), whose expression is critical for synaptic plasticity and memory. The synaptic deficits due to the loss of endogenous TRIAD3A could not be rescued by TRIAD3A harboring GHS-associated missense mutations. Moreover, we demonstrate that the loss of endogenous TRIAD3A in the mouse hippocampal CA1 region led to deficits in spatial learning and memory. Finally, we show that these missense mutations abolished the interaction of TRIAD3A with Arc, disrupting Arc ubiquitination, and consequently Arc degradation. Our current findings of Arc misregulation by TRIAD3A variants suggest that loss-of-function mutations in TRIAD3A may contribute to dementia observed in patients with GHS driven by dysfunctional UPS components, leading to cognitive impairments through the synaptic protein Arc.
authors.affiliation: Signature Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School Singapore, 8 College Road, Singapore, 169857, Singapore.
authors.forename: Nilofer
authors.initials: N
authors.lastname: Husain
authors.affiliation: Signature Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School Singapore, 8 College Road, Singapore, 169857, Singapore.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: Signature Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School Singapore, 8 College Road, Singapore, 169857, Singapore.
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Yen
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Pletnikova
authors.affiliation: Behavioral Neuroscience Laboratory, National Neuroscience Institute, 11 Jalan Tan Tock Seng, 308433, Singapore, Singapore.
authors.forename: Dong Qianying
authors.initials: DQ
authors.lastname: Sally
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Worley
authors.affiliation: Signature Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School Singapore, 8 College Road, Singapore, 169857, Singapore.|Behavioral Neuroscience Laboratory, National Neuroscience Institute, 11 Jalan Tan Tock Seng, 308433, Singapore, Singapore.
authors.forename: Zoë
authors.initials: Z
authors.lastname: Bichler
authors.affiliation: Signature Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School Singapore, 8 College Road, Singapore, 169857, Singapore.|Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore.
authors.forename: H
authors.initials: H
authors.lastname: Shawn Je
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000473:pathology; D002524:Cerebellar Ataxia / Q000235:genetics*; D002966:Clathrin / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000378:metabolism / Q000473:pathology*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004705:Endocytosis; D055785:Gene Knockdown Techniques; D007987:Gonadotropin-Releasing Hormone / Q000172:deficiency* / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011485:Protein Binding; D059748:Proteolysis; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism; D065852:Spatial Memory; D013569:Synapses / Q000378:metabolism / Q000473:pathology*; D009435:Synaptic Transmission; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D002966:Clathrin; D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; C092069:activity regulated cytoskeletal-associated protein; D007987:Gonadotropin-Releasing Hormone; C000603313:RNF216 protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: Gordon Holmes syndrome; TRIAD3; activity-regulated cytoskeletal protein (Arc/Arg 3.1); behavior; dementia; learning and memory; synapse; ubiquitination