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Developmental biology - Gene Dysfunction

Angelman syndrome due to defect on a single gene

UBE3A gene is responsible for stability in a huge number of cell processeses...

Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction which breaks peptide bonds. Enzymes that help such reactions are called proteases. Wikipedia

Ubiquitin-protein ligase E3A (UBE3A) is an enzyme that in humans is encoded by the gene UBE3A. This enzyme targets proteins to be degraded within a cell, a normal process to remove damaged or unneeded protein and maintain normal cell function. Ubiquitin-protein ligase E3A attaches a small marker protein (ubiquitin) onto proteins to be broken down. Cell structures called proteasomes recognize the marker and digest proteins tagged with ubiquitin.

Multipolar Neuron
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Both copies of the UBE3A gene are active in most of our body's tissues, except in most neurons where only the mother's copy (the maternal copy) is active. However, this recent research shows that at least some brain glial cells and neurons may also exhibit biallelic (both maternal and paternal) function of UBE3A. A more precise map is needed of how UBE3A in humans and model organisms such as mice, works. Silencing Ube3a on the paternal (father's) gene — is thought to occur due to Ube3a-ATS, part of a lincRNA called "LNCAT" for Large Non-Coding Antisense Transcript.
Angelman syndrome is a disease affecting one in every 15,000 newborn babies. It causes complex problems in the intellectual development of children, including epilepsy, difficulties in communication, lack of motor coordination and problems in balance and movement. It can also be accompanied by extremely few hours of sleep. All this because of the functional failure in the brain of the single UBE3A gene.

According to this latest research led by professor Ugo Mayor PhD, Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), there may be a new explanation for Angelman's complex symptoms. The research published in the journal Human Molecular Genetics details the mechanism affected by Angelman syndrome. Using an experimental design, UPV/EHU's General Proteomics Research Service, has managed to identify changes in brain proteins altered by a UBE3A enzyme malfunction leading to a cell's inability to break down unneeded proteins.
According to the research, UBE3A regulates the proteasomes to act as a kind of shredding machine and balance proteins within a cell.

Indirectlly, UBE3A is responsible for the stability of a huge number of processes taking place within cells. When there is an error in UBE3A, these processes cannot take place, and unneeded proteins impede the function of the cell. Until now, there was no explanation as to how a single gene could be capable of creating so many alternations in brain function.

Angelman syndrome is a complex neurodevelopmental disorder caused by the lack of function in the brain of a single gene, UBE3A. The E3 ligase coded by this gene is known to build K48-linked ubiquitin chains, a modification historically considered to target substrates for degradation by the proteasome. However, a change in protein abundance is not proof that a candidate UBE3A substrate is indeed ubiquitinated by UBE3A. We have here used an unbiased ubiquitin proteomics approach, the bioUb strategy, to identify 79 proteins that appear more ubiquitinated in the Drosophila photoreceptor cells when Ube3a is over-expressed. We found a significantly high number of those proteins to be proteasomal subunits or proteasome-interacting proteins, suggesting a wide proteasomal perturbation in the brain of Angelman patients. We focused on validating the ubiquitination by Ube3a of Rngo, a proteasomal component conserved from yeast (Ddi1) to humans (DDI1 and DDI2), but yet scarcely characterized. Ube3a-mediated Rngo ubiquitination in fly neurons was confirmed by immunoblotting. Using human neuroblastoma SH-SY5Y cells in culture, we also observed that human DDI1 is ubiquitinated by UBE3A, without being targeted for degradation. The novel observation that DDI1 is expressed in the developing mice brain, with a significant peak at E16.5, strongly suggests that DDI1 has biological functions not yet described that could be of relevance for Angelman syndrome clinical research.

Authors: Juanma Ramirez Benoit Lectez Nerea Osinalde Monika Sivá Nagore Elu Kerman Aloria Michaela Procházková Coralia Perez Jose Martínez-Hernández Rosa Barrio Klára Grantz Šašková Jesus M Arizmendi Ugo Mayor

These studies are primarily funded by the American foundation, March of Dimes, and MINECO (Spanish Ministry of Economy, Industry and Competitiveness). And by an association of relatives of people with Angelman Syndrome. The Angelman Syndrome Association is a key donor. When Dr Mayor's laboratory lacked any other backing, Angelman Syndrome Association funding was essential in enabling the project to be completed and published in the journal Human Molecular Genetics.

Ugo Mayor, an Ikerbasque professor in the UPV/EHU's Faculty of Science and Technology, wrote up his PhD thesis at Cambridge University, and after 11 years in the United Kingdom, returned to the Basque Country to work at CIC bioGUNE for 5 years. His research has been on this subject since 2012. Since 2014 his research group has been part of the Department of Biochemistry and Molecular Biology of the UPV/EHU's Faculty of Science and Technology.

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Apr 24, 2018   Fetal Timeline   Maternal Timeline   News   News Archive

Ubiquitin-protein ligase or UBE3A, is the 15th of 23 human chromosomes found in our sex cells. When sperm and egg recombine, each body cell will incorporate all 46 chromosomes. Image credit: Wikipedia

Phospholid by Wikipedia