scholarly journals Ubiquitin C-terminal hydrolase L1 (UCH-L1): structure, distribution and roles in brain function and dysfunction

2016 ◽  
Vol 473 (16) ◽  
pp. 2453-2462 ◽  
Author(s):  
Paul Bishop ◽  
Dan Rocca ◽  
Jeremy M. Henley
Keyword(s):  
Amino Acids ◽  
Neurodegenerative Disease ◽  
Brain Function ◽  
Neuronal Development ◽  
Complex Structure ◽  
Deubiquitinating Enzyme ◽  
Neuronal Function ◽  
Abundant Protein ◽  
Neuronal Protein ◽  
The Brain

Ubiquitin C-terminal hydrolase L1 (UCH-L1) is an extremely abundant protein in the brain where, remarkably, it is estimated to make up 1–5% of total neuronal protein. Although it comprises only 223 amino acids it has one of the most complicated 3D knotted structures yet discovered. Beyond its expression in neurons UCH-L1 has only very limited expression in other healthy tissues but it is highly expressed in several forms of cancer. Although UCH-L1 is classed as a deubiquitinating enzyme (DUB) the direct functions of UCH-L1 remain enigmatic and a wide array of alternative functions has been proposed. UCH-L1 is not essential for neuronal development but it is absolutely required for the maintenance of axonal integrity and UCH-L1 dysfunction is implicated in neurodegenerative disease. Here we review the properties of UCH-L1, and how understanding its complex structure can provide new insights into its roles in neuronal function and pathology.

scholarly journals Resolving rates of mutation in the brain using single-neuron genomics

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Gilad D Evrony ◽  
Eunjung Lee ◽  
Peter J Park ◽  
Christopher A Walsh
Keyword(s):  
Single Cell ◽  
Somatic Mutation ◽  
Brain Function ◽  
Single Neuron ◽  
Bioinformatic Analysis ◽  
Normal Brain ◽  
Neuronal Function ◽  
Human Neurons ◽  
Normal Brain Function ◽  
The Brain

Whether somatic mutations contribute functional diversity to brain cells is a long-standing question. Single-neuron genomics enables direct measurement of somatic mutation rates in human brain and promises to answer this question. A recent study (<xref ref-type="bibr" rid="bib65">Upton et al., 2015</xref>) reported high rates of somatic LINE-1 element (L1) retrotransposition in the hippocampus and cerebral cortex that would have major implications for normal brain function, and suggested that these events preferentially impact genes important for neuronal function. We identify aspects of the single-cell sequencing approach, bioinformatic analysis, and validation methods that led to thousands of artifacts being interpreted as somatic mutation events. Our reanalysis supports a mutation frequency of approximately 0.2 events per cell, which is about fifty-fold lower than reported, confirming that L1 elements mobilize in some human neurons but indicating that L1 mosaicism is not ubiquitous. Through consideration of the challenges identified, we provide a foundation and framework for designing single-cell genomics studies.

scholarly journals Glycolytically impaired glial cells fuel neural metabolism via β-oxidation

2021 ◽  
Author(s):  
Stefanie Schirmeier ◽  
Helen Hertenstein ◽  
Ellen McMullen ◽  
Leon Deharde ◽  
Marko Brankatschk
Keyword(s):  
Glial Cells ◽  
Brain Function ◽  
Ketone Bodies ◽  
Carbohydrate Restriction ◽  
Neuronal Function ◽  
Adverse Conditions ◽  
Energy Stores ◽  
Metabolic Sensor ◽  
The Brain ◽  
Starvation Conditions

Abstract Neuronal function is highly energy demanding and thus requires efficient and constant metabolite delivery. Like their mammalian counterparts Drosophila glia are highly glycolytic and provide lactate to fuel neuronal metabolism. However, flies are able to survive for several weeks in the absence of glial glycolysis1. Here, we study how glial cells maintain sufficient nutrient supply to neurons under conditions of carbohydrate restriction. We show that glycolytically impaired glia switch to fatty acid breakdown via β-oxidation and provide ketone bodies as an alternate neuronal fuel. Moreover, flies also rely on glial β-oxidation under starvation conditions with glial loss of β-oxidation increasing susceptibility to starvation. Further, we show that glial cells act as a metabolic sensor in the brain and can induce mobilization of peripheral energy stores to ensure brain metabolic homeostasis. In summary, our study gives pioneering evidence on the importance of glial β-oxidation and ketogenesis for brain function, and survival, under adverse conditions, like malnutrition. The glial capacity to utilize lipids as an energy source seems to be conserved from flies to humans.

scholarly journals Hyperammonaemia does not impair brain function in the absence of net glutamine synthesis

1991 ◽  
Vol 277 (3) ◽  
pp. 697-703 ◽  
Author(s):  
R A Hawkins ◽  
J Jessy
Keyword(s):  
Amino Acids ◽  
Brain Function ◽  
Aromatic Amino Acids ◽  
Preceding Paper ◽  
Glucose Consumption ◽  
High Energy ◽  
High Energy Phosphates ◽  
Intermediary Metabolites ◽  
Glutamine Synthesis ◽  
The Brain

1. It has been established that chronic hyperammonaemia, whether caused by portacaval shunting or other means, leads to a variety of metabolic changes, including a depression in the cerebral metabolic rate of glucose (CMRGlc) increased permeability of the blood-brain barrier to neutral amino acids, and an increase in the brain content of aromatic amino acids. The preceding paper [Jessy, DeJoseph & Hawkins (1991) Biochem. J. 277, 693-696] showed that the depression in CMRGlc caused by hyperammonaemia correlated more closely with glutamine, a metabolite of ammonia, than with ammonia itself. This suggested that ammonia (NH3 and NH4+) was without effect. The present experiments address the question whether ammonia, in the absence of net glutamine synthesis, induces any of the metabolic symptoms of cerebral dysfunction associated with hyperammonaemia. 2. Small doses of methionine sulphoximine, an inhibitor of glutamine synthetase, were used to raise the plasma ammonia levels of normal rats without increasing the brain glutamine content. These hyperammonaemic rats, with plasma and brain ammonia levels equivalent to those known to depress brain function, behaved normally over 48 h. There was no depression of cerebral energy metabolism (i.e. the rate of glucose consumption). Contents of key intermediary metabolites and high-energy phosphates were normal. Neutral amino acid transport (tryptophan and leucine) and the brain contents of aromatic amino acids were unchanged. 3. The data suggest that ammonia is without effect at concentrations less than 1 mumol/ml if it is not converted into glutamine. The deleterious effect of chronic hyperammonaemia seems to begin with the synthesis of glutamine.

scholarly journals Modeling Emergent Properties in the Brain Using Tissue Models to Investigate Neurodegenerative Disease

2019 ◽  
Vol 26 (3) ◽  
pp. 224-230
Author(s):  
Alexander R. Harris ◽  
Patrick McGivern ◽  
Lezanne Ooi
Keyword(s):  
Neurodegenerative Disease ◽  
Brain Function ◽  
Emergent Properties ◽  
In Vitro Modeling ◽  
Tissue Models ◽  
The Brain

Here we describe emergent properties of the brain and the key challenges associated with modelling them in vitro. Modeling emergent properties of the brain will provide insights into brain function, development, and disease.

scholarly journals Brief freezing steps lead to robust immunofluorescence in the Drosophila nervous system

BioTechniques ◽  
2019 ◽  
Vol 67 (6) ◽  
pp. 299-305
Author(s):  
Ada Thapa ◽  
Shea M Sullivan ◽  
Minh Q Nguyen ◽  
Dominic Buckley ◽  
Vy T Ngo ◽  
...  
Keyword(s):  
Nervous System ◽  
Drosophila Melanogaster ◽  
Neurodegenerative Disease ◽  
Spatial Organization ◽  
Molecular Mechanisms ◽  
Structural Integrity ◽  
Antibody Specificity ◽  
Proteolytic Digestion ◽  
Neuronal Function ◽  
The Brain

Drosophila melanogaster possesses a complex nervous system, regulating sophisticated behavioral outputs, that serves as a powerful model for dissecting molecular mechanisms underlying neuronal function and neurodegenerative disease. Immunofluorescence techniques provide a way to visualize the spatiotemporal organization of these networks, permitting observation of their development, functional location, remodeling and, eventually, degradation. However, basic immunostaining techniques do not always result in efficient antibody penetration through the brain, and supplemental techniques to enhance permeability can compromise structural integrity, altering spatial organization. Here, slow freezing of brains is shown to facilitate antibody permeability without loss of antibody specificity or brain integrity. To demonstrate the advantages of this freezing technique, the results of two commonly used permeation methods – detergent-based and partial proteolytic digestion – are compared.

scholarly journals Ubiquitin C-terminal hydrolase L1 (UCH-L1) loss causes neurodegeneration by altering protein turnover in the first postnatal weeks

2019 ◽  
Vol 116 (16) ◽  
pp. 7963-7972 ◽  
Author(s):  
Anna T. Reinicke ◽  
Karoline Laban ◽  
Marlies Sachs ◽  
Vanessa Kraus ◽  
Michael Walden ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Protein Turnover ◽  
Neuronal Development ◽  
Postnatal Period ◽  
Neuronal Function ◽  
Neuronal Protein ◽  
Neurological Phenotype ◽  
Deficient Mice

Ubiquitin C-terminal hydrolase L1 (UCH-L1) is one of the most abundant and enigmatic enzymes of the CNS. Based on existing UCH-L1 knockout models, UCH-L1 is thought to be required for the maintenance of axonal integrity, but not for neuronal development despite its high expression in neurons. Several lines of evidence suggest a role for UCH-L1 in mUB homeostasis, although the specific in vivo substrate remains elusive. Since the precise mechanisms underlying UCH-L1–deficient neurodegeneration remain unclear, we generated a transgenic mouse model of UCH-L1 deficiency. By performing biochemical and behavioral analyses we can show that UCH-L1 deficiency causes an acceleration of sensorimotor reflex development in the first postnatal week followed by a degeneration of motor function starting at periadolescence in the setting of normal cerebral mUB levels. In the first postnatal weeks, neuronal protein synthesis and proteasomal protein degradation are enhanced, with endoplasmic reticulum stress, and energy depletion, leading to proteasomal impairment and an accumulation of nondegraded ubiquitinated protein. Increased protein turnover is associated with enhanced mTORC1 activity restricted to the postnatal period in UCH-L1–deficient brains. Inhibition of mTORC1 with rapamycin decreases protein synthesis and ubiquitin accumulation in UCH-L1–deficient neurons. Strikingly, rapamycin treatment in the first 8 postnatal days ameliorates the neurological phenotype of UCH-L1–deficient mice up to 16 weeks, suggesting that early control of protein homeostasis is imperative for long-term neuronal survival. In summary, we identified a critical presymptomatic period during which UCH-L1–dependent enhanced protein synthesis results in neuronal strain and progressive loss of neuronal function.

Seeing the Brain in Action: How Multiphoton Imaging Has Advanced Our Understanding of Neuronal Function

2008 ◽  
Vol 14 (6) ◽  
pp. 482-491 ◽  
Author(s):  
Grace Stutzmann
Keyword(s):  
Brain Function ◽  
Structural Information ◽  
Multiphoton Microscopy ◽  
Biological Research ◽  
Neuronal Function ◽  
Multiphoton Imaging ◽  
New Era ◽  
The Brain ◽  
Insight Into ◽  
Gaining Insight

AbstractGaining insight into how the nervous system functions is a challenge for scientists, particularly because the static morphology of the brain and the cells within tell little about how they actually work. Fixed specimens can provide critical structural information, but the jump to functional neurobiology in living cells is obviated with these preparations. In order to grasp the complexity of neuronal activity, it is necessary to observe the brain in action, from the level of subcellular signaling to the whole organism. Recent advances in nonlinear microscopy have given rise to a new era for biological research. In particular, the introduction of multiphoton excitation has drastically improved the depth and speed to which we can probe brain function. In order to better appreciate recent contributions of multiphoton microscopy to our current and future understanding of biological systems, an historical awareness of past microscopy applications is useful.

scholarly journals Brief Freezing Steps Lead to Robust Immunofluorescence in Drosophila Larval Brains

2018 ◽  
Author(s):  
Dominic Buckley ◽  
Ada Thapa ◽  
Minh Q. Nguyen ◽  
Essence Blankinship ◽  
Diana Williamson ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Neurodegenerative Disease ◽  
Molecular Mechanisms ◽  
Structural Integrity ◽  
Proteolytic Degradation ◽  
Antibody Specificity ◽  
Neuronal Function ◽  
Larval Brain ◽  
Apparent Loss ◽  
The Brain

AbstractDrosophila melanogaster possess complex neuronal networks regulating sophisticated behavioral outputs that aid in studying the molecular mechanisms of neuronal function and neurodegenerative disease. Immunofluorescence (IF) techniques provide a way to visualize the spatiotemporal organization of these networks, permitting observation of their development, functional location, remodeling, and eventually - degradation. However, general immunostaining techniques do not always result in sufficient antibody penetration through the brain, and techniques used to enhance permeability can compromise structural integrity. We have found that freezing larval brains facilitates permeability with no apparent loss of antibody specificity or structural integrity. To demonstrate the advantage of this freezing technique, we compared results to two commonly used permeation methods: Detergent alone (Basic) and proteolytic degradation (Collagenase) techniques.SummaryHere we compare four different immunofluorescence techniques demonstrating that freezing Drosophila brains results in robust staining of small neurons in the larval brain without compromising structural integrity.

Frontier concept of rabi chip for intelligent humanoid

2018 ◽  
Vol 1 (2) ◽  
Author(s):  
Preecha Yupapin ◽  
Amiri I. S. ◽  
Ali J. ◽  
Ponsuwancharoen N. ◽  
Youplao P.
Keyword(s):  
Human Brain ◽  
Brain Function ◽  
Rabi Oscillation ◽  
Liquid Core ◽  
Brain Surface ◽  
Dipole Oscillation ◽  
On Chip ◽  
The Brain ◽  
Robotic Applications ◽  
Atom System

The sequence of the human brain can be configured by the originated strongly coupling fields to a pair of the ionic substances(bio-cells) within the microtubules. From which the dipole oscillation begins and transports by the strong trapped force, which is known as a tweezer. The tweezers are the trapped polaritons, which are the electrical charges with information. They will be collected on the brain surface and transport via the liquid core guide wave, which is the mixture of blood content and water. The oscillation frequency is called the Rabi frequency, is formed by the two-level atom system. Our aim will manipulate the Rabi oscillation by an on-chip device, where the quantum outputs may help to form the realistic human brain function for humanoid robotic applications.

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