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UBA6: An E1 enzyme critical for hippocampal and amygdalar development

Contributed by Jill R. Glausier, Ph.D.

Protein turnover and degradation is an essential component for the proper functioning of all eukaryotic cells. Proteins are tagged for degradation by the addition of ubiquitin, a process which requires three distinct enzyme classes. The classes are E1, the ubiquitin-activating enzyme; E2, the ubiquitin-conjugating enzymes; and E3, the ubiquitin-protein ligases. Although many E2 and E3 enzymes exist, the canonical ubiquitination pathway has only one ubiquitin-activating E1 enzyme, termed UBE1. However, within the last decade, researchers have identified a second ubiquitin-activating E1 enzyme, termed UBA1, 2, 3. UBA6 has both distinct and overlapping traits with UBE1. For example, these enzymes are able to activate ubiquitin but UBA6 is also able to activate the ubiquitin-like modifier, FAT10. Both E1 enzymes can interact with a population of E2 enzymes but only UBA6 interacts with the E2 enzyme USE14.

In a recent study to assess the role of UBA6 in the brain, the authors generated transgenic mice that lacked the Uba6 gene in neurons (Uba6NKO mice)5. This gene knock-out was associated with significant postnatal lethality that was largely rectified by providing mice with easier access to food. At 3 months of age, the CA3 region of the hippocampus and the basolateral amygdala (BLA) were profoundly and preferentially affected. Neuronal density was reduced by 60% and 40%, respectively, and the distinctive morphology of CA3 was disturbed. Interestingly, the reduced neuronal density did not appear to reflect an increase in apoptosis and may be a consequence of fewer neurons being born or defective neuronal migration. The remaining hippocampal and BLA neurons within Uba6NKO mice showed significant reductions in dendritic spine density, especially within the BLA, where neurons had 45% fewer spines per dendritic length relative to control mice.

As dendritic spines are the site of the vast majority of synapses within the brain, and because spine dysfunction has been linked to a variety of neurological and psychiatric illnesses, the authors performed a battery of behavioral tests6, 7. These showed that the Uba6NKO mice exhibited impaired learning and memory phenotypes, increased anxiety-like behaviors, hyperactivity, and impaired social behaviors. Moreover, the mice showed some abnormal fear-conditioning behaviors, consistent with altered amygdalar function. Given the significant reduction in dendritic spine density and consequent behavioral abnormalities, the authors quantified a battery of proteins important for spine formation and maintenance. Of particular interest in this study, the expression of SHANK3, a key postsynaptic density scaffolding protein8, and UBE3A, an E3 ubiquitin-ligase, was significantly increased in Uba6NKO mice. UBE3A mutations have been found to cause Angelman’s Syndrome, a developmental disorder characterized by pronounced intellectual disability, hyperactive movements, and an easily excitable and happy disposition9. Together, these results indicate that: 1) UBA6 is a lynchpin for spine formation or maintenance, 2) UBA6 and UBE3A work together in the ubiquitination pathway, and 3) SHANK3 is a likely target of UBA6 ubiquitination pathways.

In sum, this recent study points to exciting new avenues of research for investigating the precise roles of UBA6 and ubiquitination pathways in brain maturation and function for both healthy development and multiple neurological as well as psychiatric illnesses.


Detection of human UBA6 by WB of 293T, HeLa, and Jurkat lysate.

Detection of human UBA6 by WB of 293T, HeLa, and Jurkat lysate. Antibody: Rabbit anti-UBA6 (A304-109A). Secondary: HRP-conjugated goat anti-rabbit IgG (A120-101P).

Detection of human E6AP/UBE3A by WB of immunoprecipitates from 293T, HeLa, and Jurkat lysate.

Detection of human E6AP/UBE3A by WB of immunoprecipitates from 293T, HeLa, and Jurkat lysate. Antibodies: Rabbit anti- E6AP/UBE3A (A300-351A) and rabbit anti-53BP1 (A300-272A). Secondary: ReliaBLOT® reagents (WB120).

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