Dysfunction of the ubiquitin ligase Ube3a may be associated with synaptic pathophysiology in a mouse model of Huntington disease.
Huntington disease (HD) is a hereditary neurodegenerative disorder characterized by progressive cognitive, psychiatric, and motor symptoms. The disease is caused by abnormal expansion of CAG repeats in the gene encoding huntingtin, but how mutant huntingtin leads to early cognitive deficits in HD is poorly understood. Here, we demonstrate that the ubiquitin ligase Ube3a, which is implicated in synaptic plasticity and involved in the clearance of misfolded polyglutamine protein, is strongly recruited to the mutant huntingtin nuclear aggregates, resulting in significant loss of its functional pool in different regions of HD mouse brain. Interestingly, Arc, one of the substrates of Ube3a linked with synaptic plasticity, is also associated with nuclear aggregates, although its synaptic level is increased in the hippocampus and cortex of HD mouse brain. Different regions of HD mouse brain also exhibit decreased levels of AMPA receptors and various pre- and postsynaptic proteins, which could be due to the partial loss of function of Ube3a. Transient expression of mutant huntingtin in mouse primary cortical neurons further demonstrates recruitment of Ube3a into mutant huntingtin aggregates, increased accumulation of Arc, and decreased numbers of GluR1 puncta in the neuronal processes. Altogether, our results suggest that the loss of function of Ube3a might be associated with the synaptic abnormalities observed in HD.
Cellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon, Haryana 122050, India.
Megha
M
Maheshwari
Ananya
A
Samanta
Swetha K
SK
Godavarthi
Rajarshi
R
Mukherjee
Nihar Ranjan
NR
Jana
D000818:Animals; D002540:Cerebral Cortex / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009473:Neuronal Plasticity / Q000235:genetics; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D017510:Protein Folding; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019680:Trinucleotide Repeat Expansion; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D003598:Cytoskeletal Proteins; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D018091:Receptors, AMPA; D044767:Ubiquitin-Protein Ligases; C086055:HTT protein, human; C506812:Htt protein, mouse; C092069:activity regulated cytoskeletal-associated protein; C471639:UBE3A protein, human; C502429:Ube3a protein, mouse