Open AccessTRIAD3/RNF216 mutations associated with Gordon Holmes syndrome lead to synaptic and cognitive impairments via Arc misregulation
Author(s) -
Husain Nilofer,
Yuan Qiang,
Yen YiChun,
Pletnikova Olga,
Sally Dong Qianying,
Worley Paul,
Bichler Zoë,
Shawn Je H.
Publication year - 2017
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12551
Subject(s) - arc (geometry) , ubiquitin ligase , missense mutation , biology , loss function , ubiquitin , synaptic plasticity , neuroscience , mutation , hippocampus , hippocampal formation , microbiology and biotechnology , genetics , receptor , gene , phenotype , geometry , mathematics
Summary Multiple loss‐of‐function mutations in TRIAD 3 (a.k.a. RNF 216) have recently been identified in patients suffering from Gordon Holmes syndrome ( GHS ), characterized by cognitive decline, dementia, and movement disorders. TRIAD 3A 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 TRIAD 3 (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 TRIAD 3A could not be rescued by TRIAD 3A harboring GHS ‐associated missense mutations. Moreover, we demonstrate that the loss of endogenous TRIAD 3A in the mouse hippocampal CA 1 region led to deficits in spatial learning and memory. Finally, we show that these missense mutations abolished the interaction of TRIAD 3A with Arc, disrupting Arc ubiquitination, and consequently Arc degradation. Our current findings of Arc misregulation by TRIAD 3A variants suggest that loss‐of‐function mutations in TRIAD 3A may contribute to dementia observed in patients with GHS driven by dysfunctional UPS components, leading to cognitive impairments through the synaptic protein Arc.