Hormone und Selenoproteine

Research

Our research covers two principal areas of research: hormones and selenoproteins.

Thyroid hormone action and metabolism

In the field of thyroid hormone action and metabolism, we are interested in mechanism that regulate the availability of T3 in the cell before it can bind its nuclear receptor. Hence, we are interested in MCT8, a solute carrier protein, that helps thyroid hormones to cross the plasma membrane. Mutations in MCT8, lead to severe intellectual disability in patients. Another facet of pre-receptor regulation of thyroid hormone action pertains to local adjustment of T3 levels by the action of iodothyronine deiodinases, enzymes that are capable of activation and inactivation of thyroid hormones. We are interested in their structure and function. Deiodinases are selenium-containing proteins, which connects them with our second area of research.

Selenoproteins are proteins containing the rare amino acid selenocysteine (Sec). We are mainly interested in what selenoproteins are doing in the brain and how they are made. Since Sec is encoded by a UGA codon in the mRNA, a mechanism exists which prevents termination and favors elongation at the UGA/Sec codon. We are curious how this works and recently adopted the RiboSeq method in order to study the process more precisely.

AG_Schweizer_1
© Ulrich Schweizer

Eine Wissenschaftlerin und ein Wissenschaftler arbeiten hinter einer Glasfassade und mischen Chemikalien mit Großgeräten.
© AG Schweizer

Rare, but essential – the amino acid selenocysteine

Based at the University of Bonn, Germany, Professor Dr Ulrich Schweizer is leading research into revealing the role of selenoproteins in mammalian physiology. By elucidating the mechanisms underlying their function, his work is yielding new insights into a wide array of human diseases affecting the brain and thyroid hormones. At the core of Prof Dr Schweizer’s research is the rare selenium-containing 21st amino acid selenocysteine (Sec), the defining component of selenoproteins.

Selenocysteine (Sec) is an essential amino acid component in selenoproteins, which are involved in a variety of cellular and metabolic processes. Increasingly, their deregulation is being associated with neurodegenerative and other diseases, for which the underlying mechanisms have remained unclear. However, using novel transgenic mouse models, Prof Dr Schweizer and his team have uncovered a wealth of information regarding the mechanisms behind their function. His team’s extensive research has found that reducing the expression of selenoproteins in the mammalian brain impairs brain development and healthy functioning, consequently causing a broad spectrum of disorders, including epilepsy and neurodegeneration. Selenoproteins are proteins within which Sec is incorporated in the polypeptide chain. The importance of Sec had, until recently, been overlooked – perhaps due to its low abundance and discovery after the other 20 canonical amino acids. In Sec, an atom of the trace element selenium (Se) replaces the sulphur atom of cysteine. Selenium possesses similar but more reactive properties than sulphur, and is always housed in the active centre of selenoenzymes.

INVESTIGATING THE RAREST AMINO ACID

Sec eluded the Nobel Prize winning scientists who deciphered the genetic code, because Sec is encoded by what has been regarded exclusively as a termination codon, UGA. How can the cell distinguish between termination and Sec incorporation? There is a specific element within the mRNA sequence that directs the re-coding of UGA, called the selenocysteine insertion sequence (SECIS). The SECIS is recognised by a SECIS-binding protein, which in turn instructs the ribosome not to terminate but to incorporate Sec – see the figure overleaf. The human genome contains 25 selenoprotein-coding genes. Mice have the same selenoprotein genes as humans, but one less. Out of the selenoproteins encoded by the human and rodent genomes, around half of their functions remain unknown. Dr Schweizer and other scientists realised that the genetic analysis of transgenic mice in which specific gene function has been disrupted or altered could shed light on the roles of individual selenoproteins. In fact, several selenoproteins are essential for mammals. With the rapid development of human genetics more and more mutations have been identified in humans that disrupt selenoprotein function.

SELENIUM AT THE CORE OF CRUCIAL ENZYME ACTIVE SITES

Proteins that function as enzymes, in which Sec is a key component, are known as selenoenzymes. These are most established as anti-oxidative enzymes that fight ‘free radicals’ within cells, and are therefore implicated in ageing and metabolic disorders. In addition, selenium and the selenoenzymes it is incorporated into, are critical to the regulation of thyroid hormone activity. This became apparent when patients with mutations in the SECIS-binding protein were found to have growth delay and blunted response to thyroid hormones. Both can be explained by Sec's presence in deiodinases. Deiodinases are a group of selenoenzymes that are responsible for the activation and deactivation of thyroid hormones on the tissue level. Thyroid hormones are known to be central to development and play a key role in energy expenditure and metabolism and, as discovered more recently, play crucial roles in stem cells, regeneration, and cancer. How deiodinases work exactly remained poorly understood, until Dr Schweizer teamed up with protein crystallographers to become the first team to solve the crystal structure of one of these enzymes. Quite remarkably, the enzyme resembles ancient peroxide-degrading enzymes and must have acquired its vertebrate-specific function after losing its original function.

SURPRISING PHENOTYPE SHIFTS FOCUS TO NEURONAL DEVELOPMENT AND DEGENERATION

While completing his PhD on another topic, Dr Schweizer discovered that one of the knockout mice he had created was epileptic, sparking his realisation that selenoproteins may be of vital importance to brain function. Since then, Dr Schweizer and his researchers have embarked on a project to investigate the role of selenoproteins in neuronal function, looking at how they are implicated in neurological disease. Prior to this discovery, only few earlier reports had highlighted the potential link between epilepsy and low levels of selenium in the blood. During this time though, the majority of selenoprotein functions remained uncategorised, and therefore the connection to selenocysteine had not been made. Prof Dr Schweizer and his team’s research has since found that selenoproteins are essential for brain development, and they have succeeded in working out some of the specific mechanisms involved. They have identified a specific class of GABAergic interneurons, in which dysfunction is fundamental to the clinical manifestation of epilepsy, finding that two selenoproteins are intrinsically linked to this process. To do this, Prof Dr Schweizer and his team disrupted neuronal selenoprotein biosynthesis in their mice models, deleting the gene that encodes the tRNA essential for Sec biosynthesis. When specifically inactivated in the neurons, the researchers discovered a developmental defect affecting a specific subgroup of inhibitory interneurons. This found that there was not only a reduction of interneurons, but the mice also suffered from seizures and ataxia, a failure to gain postural control, and a failure to coordinate their movements. Histological analysis of the mouse brain tissue showed progressive neurodegeneration underlying these phenotypes. Work on other mutant mouse models revealed that cellular glutathione peroxidase (GPX4) and cytosolic thioredoxin reductase (TXRND1) were involved in this process. Very recently, Dr Schweizer’s research has revealed that mutations in the gene for TXNRD1 are present in patients with generalised epilepsy. Moreover, patients with congenital mutations in the selenocysteine synthase gene have been found to suffer from a complex neurodevelopmental and degenerative disorder that involves a wide spectrum of features, including microcephaly, delayed intellectual and motor development, spasticity and epileptic seizures. Recently, patients have been identified carrying very mild mutations in the gene explaining why they are only afflicted with lower IQ, but do not suffer any neurodegeneration.

INBORN ERRORS IN SELENOPROTEINS LINKED TO WIDE ARRAY OF DISORDERS

Other disorders, in addition to epilepsy and neurodegeneration, have also been linked to mutations in selenoprotein genes. For example, mutations in selenoprotein N (SEPN1) result in a spectrum of muscular disorders, which are known collectively as SEPN1-related myopathy. It is likely that, as the function of selenoproteins becomes better understood, many more rare diseases caused by selenoprotein deficiency will soon be uncovered. Prof Dr Schweizer and his team are hopeful that their research will open up new avenues for the diagnosis and treatment of neurodegenerative diseases.

Q & A

Selenium is unique in that selenoproteins have selenium attached by stable chemical bonds – making analysis much easier than for example zinc, which is less tightly bound. Also, selenoproteins can be detected based on genome sequences. So identification of a selenoprotein in rattle snakes or polar bears does not require wet chemistry. Another advantage is the limited number of selenoproteins. Roughly two dozen selenoprotein genes foster my hope to finally understand all their functions within my lifetime.

To many people's surprise, no. Colleagues often assume that research in the selenium field is hard to get funded. This is not correct, at least in my case, probably because we are not doing nutritional science, but hard-core molecular biology and biochemistry. But it is true, if you say you work on Alzheimer’s, stem cells or cancer, one catch word is often enough to explain yourself...

One reason might be that a selenoenzyme may be 1000-fold faster than the same enzyme with cysteine. For complex cells, like ours, the selenoenzyme thus saves a lot of space that can be occupied by other enzymes doing other things. Ask yourself: Would you rather invite five smart people home for dinner or instead five thousand boring guests?

This is too early at this moment, but I firmly believe that biochemistry helps to i) diagnose disorders, ii) understand their pathomechanisms, and with this knowledge iii) guides rational treatment strategies. There are many very good examples in the medical field for this opinion, among them all the inherited disorders that are included in the perinatal screening programmes which help many kids get the right treatment in time and thus prevent the development of severe mental disability.

Clearly, I would like to further delineate the functions of selenoproteins in the brain and find out what exactly each selenoprotein does in each brain cell type and how. In addition, I have recently started to investigate the biochemistry of selenoprotein biosynthesis, i.e., how exactly the ribosome is instructed to incorporate Sec – instead of terminating protein biosynthesis. Along these lines, we are studying the function of the tRNA carrying Sec, which has recently been found to be mutated in a patient with abnormal response to thyroid hormone.


Funding

We receive(d) funding from the DFG (Einzelanträge, Schwerpunktprogramm 1087, SFB 665/A7, Graduate College 1208, Schwerpunktprogramm THYROID TRANS ACT, Sherman Foundation, German Israeli Fund).


Current Research interests

  • Functions of selenoproteins within the brain
  • Biosynthesis of selenoproteins
  • Catalytic mechanism of deiodinases
  • Thyroid hormone transport via MCT8; response of mutant MCT8 to chemical chaperones
  • tRNA modification (isopentenylation) and fidelity of translation (ribosomal profiling)

Lesen Sie auch

Team

We welcome students from Human Medicine, Dentistry, and any area of molecular biology and biochemistry.

Prof. Dr. Ulrich Schweizer

Publications

We believe that research is important, but of minimal impact, if you don’t share your findings with the world.

Wird geladen