Sodium-potassium ATPase emerges as a player in hippocampal phenotypes of Angelman syndrome mice.

Angelman syndrome is a neurodevelopmental disorder characterized by intellectual disabilities, ataxia, and unusually happy affect. The hippocampal pyramidal cells of Angelman syndrome model mice have altered intrinsic membrane properties, which Kaphzan et al. (Cell Rep 4: 405-412, 2013) demonstrate can be corrected by genetic reduction of the α1-subunit of the sodium-potassium ATPase. Intriguingly, this manipulation also restores hippocampal long-term potentiation and learning. In this Neuro Forum, we discuss translational implications of this work and remaining questions left in its wake.

A catalytic independent function of the deubiquitinating enzyme USP14 regulates hippocampal synaptic short-term plasticity and vesicle number.

The ubiquitin proteasome system is required for the rapid and precise control of protein abundance that is essential for synaptic function. USP14 is a proteasome-bound deubiquitinating enzyme that recycles ubiquitin and regulates synaptic short-term synaptic plasticity. We previously reported that loss of USP14 in ax(J) mice causes a deficit in paired pulse facilitation (PPF) at hippocampal synapses. Here we report that USP14 regulates synaptic function through a novel, deubiquitination-independent mechanism. Although PPF is usually inversely related to release probability, USP14 deficiency impairs PPF without altering basal release probability. Instead, the loss of USP14 causes a large reduction in the number of synaptic vesicles. Over-expression of a catalytically inactive form of USP14 rescues the PPF deficit and restores synaptic vesicle number, indicating that USP14 regulates presynaptic structure and function independently of its role in deubiquitination. Finally, the PPF deficit caused by loss of USP14 can be rescued by pharmacological inhibition of proteasome activity, suggesting that inappropriate protein degradation underlies the PPF impairment. Overall, we demonstrate a novel, deubiquitination-independent function for USP14 in influencing synaptic architecture and plasticity.

Genetic background alters the severity and onset of neuromuscular disease caused by the loss of ubiquitin-specific protease 14 (usp14).

In this study, we identified and characterized an N-ethyl-N-nitrosourea (ENU) induced mutation in Usp14 (nmf375) that leads to adult-onset neurological disease. The nmf375 mutation causes aberrant splicing of Usp14 mRNA, resulting in a 95% reduction in USP14. We previously showed that loss of USP14 in ataxia (ax (J)) mice results in reduced ubiquitin levels, motor endplate disease, Purkinje cell axonal dystrophy and decreased hippocampal paired pulse facilitation (PPF) during the first 4-6 weeks of life, and early postnatal lethality by two months of age. Although the loss of USP14 is comparable between the nmf375 and ax (J) mice, the nmf375 mice did not exhibit these ax (J) developmental abnormalities. However, by 12 weeks of age the nmf375 mutants present with ubiquitin depletion and motor endplate disease, indicating a continual role for USP14-mediated regulation of ubiquitin pools and neuromuscular junction (NMJ) structure in adult mice. The observation that motor endplate disease was only seen after ubiquitin depletion suggests that the preservation of NMJ structure requires the stable maintenance of synaptic ubiquitin pools. Differences in genetic background were shown to affect ubiquitin expression and dramatically alter the phenotypes caused by USP14 deficiency.

The ubiquitin-specific protease 14 (USP14) is a critical regulator of long-term memory formation.

Numerous studies have suggested a role for ubiquitin-proteasome-mediated protein degradation in learning-dependent synaptic plasticity; however, very little is known about how protein degradation is regulated at the level of the proteasome during memory formation. The ubiquitin-specific protease 14 (USP14) is a proteasomal deubiquitinating enzyme that is thought to regulate protein degradation in neurons; however, it is unknown if USP14 is involved in learning-dependent synaptic plasticity. We found that infusion of a USP14 inhibitor into the amygdala impaired long-term memory for a fear conditioning task, suggesting that USP14 is a critical regulator of long-term memory formation in the amygdala.

Neuronal ubiquitin homeostasis.

Neurons have highly specialized intracellular compartments that facilitate the development and activity of the nervous system. Ubiquitination is a post-translational modification that controls many aspects of neuronal function by regulating protein abundance. Disruption of this signaling pathway has been demonstrated in neurological disorders such as Parkinson's disease, Amyotrophic Lateral Sclerosis and Angleman Syndrome. Since many neurological disorders exhibit ubiquitinated protein aggregates, the loss of neuronal ubiquitin homeostasis may be an important contributor of disease. This review discusses the mechanisms utilized by neurons to control the free pool of ubiquitin necessary for normal nervous system development and function as well as new roles of protein ubiquitination in regulating the synaptic activity.

An association between eating disorder behaviors and autonomic dysfunction in a nonclinical population. A pilot study.

This pilot study examines the relationship between eating disorder behaviors and autonomic dysfunction in a nonclinical sample (n = 27). Baseline indices of eating disorder behaviors were evaluated via the Eating Disorder Examination-Questionnaire. Supine resting heart rate variability was assessed via electrocardiogram for a 5-min recording period. A spectral analysis was performed. High frequency power density (s2/Hz) increased as a function of heightened disordered eating behaviors. Autonomic dysfunction, as indicated by increased high frequency power density due to hypervagal activity, is associated with eating disorder behaviors. Results suggest autonomic dysfunction may exist in nonclinical eating disorder populations. Future research needs to further examine this possibility.

Eating disorder behaviors and depression: a minimal relationship beyond social comparison, self-esteem, and body dissatisfaction.

Existing literature fails to comprehensively identify factors contributing to the comorbid relationship between eating disorder (ED) behaviors and unipolar depression. Maladaptive social comparison, body dissatisfaction, and low self-esteem are disruptive psychological patterns common to both constructs. It is unclear whether a unique relationship exists between depression and eating disorder behaviors beyond the effects exerted by this negative cognitive triad. The purpose of the present study is to examine whether a unique relationship exists between depression and ED behaviors after controlling for maladaptive social comparison, body dissatisfaction, and low self-esteem. We predict minimal unique variance in ED behaviors will be explained by depression after controlling for this negative cognitive triad.

Accumulation of BEL1-like transcripts in solanaceous species.

Although numerous RNAs have been detected in the phloem, only a few have been confirmed to move long distances. In potato, full-length mRNA of the BEL1-like transcription factor, StBEL5, moves from leaf veins through the phloem to stolon tips to activate tuber formation. BEL1-like transcription factors are ubiquitous in plants and interact with KNOTTED1-types to regulate numerous developmental processes. To explore the range of KNOTTED1- and BEL1-like mRNAs present in phloem, an analysis of the transcript profile of phloem sap was undertaken. Using a modified technique for the collection of phloem-enriched exudate from excised stems, numerous RNAs encoding these transcription factors were detected in the phloem sap from several solanceous species. All seven known BEL1-like RNAs of potato were detected in the phloem-enriched exudates of stem, whereas several stolon-abundant RNAs were not. After refining the technique to minimize the contamination from RNA arising from wounded cells, KNOTTED1-like RNAs were detected in phloem-enriched sap of potato and BEL5 RNA was detected in the sap collected from two closely related nontuber-bearing potato species and tomato. BEL5 RNA was also detected in RNA extracted from leaf veins of tobacco. The detection of these full-length mRNAs from the KNOTTED1- and BEL1-like families in phloem sap indicates that their potential role as long-distance signals seems to be much more extensive than previously known.

Femininity and eating disorders.

The purpose of this study is to examine conformity to traditional feminine norms as a predictor of eating disorder (ED) symptomatology. Eight subscales of the Conformity to Feminine Norms Inventory (CFNI) were examined as predictors of ED symptomatology as assessed by the Eating Disorder Examination-Questionnaire (EDE-Q). Findings indicate the Thinness subscale of the CFNI predicted significant portions of the variance in ED symptomatology. Contrary to the findings of Mahalik and colleagues (2005), no other CFNI subscales predicted ED symptoms. Implications for the femininity theory of EDs are discussed.