Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

FMP and MDC Researchers Identify a Fundamental Process in Lysosomal Function and Protein Degradation

16.06.2010
The degradation of proteins and other macromolecules in cells is vital to survival. Disruption of this process can result in serious disease.

The research group of Professor Thomas Jentsch (Leibniz Institute for Molecular Pharmacology, FMP/ Max Delbrück Center for Molecular Medicine, MDC, Berlin-Buch) has now succeeded in identifying an essential cellular process necessary for the transport and degradation of macromolecules in endosomes and lysosomes, respectively. In two studies published in the same issue of Science, they showed that contrary to scientific consensus the function of these cell organelles not only depends on the pH, but also on chloride ion accumulation in their interior.*

Proteins are the building blocks and machines of life. Tens of thousands of them are present in each cell, where they perform essential tasks for the organism. Once they have fulfilled their function, they must be degraded to avoid causing damage. One way in which proteins can be degraded is via the digestion processes inside tiny cellular organelles, the lysosomes. The transport of the proteins destined for degradation to these cellular “trash bins” is partly carried out by endosomes, which deliver proteins from the cell surface to the cell interior.

The functionality of both endosomes and lysosomes depends on the ion concentration within their membrane-enclosed interior. In particular, an important role is ascribed to a high concentration of hydrogen ions, i.e. an acidic pH, inside those organelles.

The two studies by Dr. Stefanie Weinert, Dr. Gaia Novarino and Professor Thomas Jentsch focus on two ion transport proteins, the chloride transporters ClC-5 and ClC-7. These are located in the membrane of endosomes and/or lysosomes and exchange negatively charged chloride ions for positively charged hydrogen ions (protons).

ClC-5 is located in the membrane of endosomes in renal cells. If ClC-5 is defective or lacking altogether, proteins can hardly be absorbed from the urine any longer. In a cascade of indirect mechanisms, this leads to the development of kidney stones in Dent’s disease.

ClC-7 is located in the membrane of lysosomes in all cells of the body. The research group by Thomas Jentsch showed already a few years ago that mutations of ClC-7 in mice and humans lead to severe disease symptoms. Impaired lysosomal function in the brain results in severe degenerative changes that leads to massive neuronal death. A dysfunction of bone-degrading osteoclasts causes an excessive calcification of bones (osteopetrosis).

The chloride-proton exchangers ClC-5 and ClC-7 function parallel to proton pumps, which ensures an acidic environment within endosomes and lysosomes. ClC-5 and ClC-7 transport chloride ions into these organelles, thereby electrically balancing the inward transport of positively charged protons through the “pump”. Hitherto researchers had assumed that maintaining the charge balance was the sole task of ClC-5 and ClC-7, without which both the transport of endosomes and lysosomal protein degradation are impaired.

However, Professor Jentsch and his team showed several years ago that the pH in lysosomes devoid of ClC-7 is normal and that nevertheless lysosomal storage disease and osteopetrosis ensue. This means that charge balancing in lysosomes may involve a different, previously unknown mechanism, and that the main task of ClC-7 may rather be the regulation of lysosomal chloride concentration. The Berlin research group proposed that the exchange of chloride for protons, which are more highly concentrated in the acidic environment of lysosomes than in the rest of the cell, accumulates chloride ions in lysosomes. A high lysosomal chloride concentration may be functionally important.

“In an elegant experimental approach” as Professor Jentsch explains the test of this hypothesis, “Dr. Novarino and Dr. Weinert converted the ClC-5 and ClC-7 chloride-proton exchangers in the mouse into pure chloride conductors (channels). They exchanged a single amino acid out of a total of around 800 present in the ion transporters”. These mutated transport proteins are optimally suited to compensate the charge transfer by the proton pump and therefore should, according to the hypothesis of the research group, support the acidification of the organelles very well.

On the other hand, the uncoupling of chloride transport from proton transport should significantly lower the accumulation of chloride into these organelles. Indeed, this prediction was confirmed experimentally in their mouse model. “Surprisingly,” Professor Jentsch said, “the corresponding mice showed almost the same disease symptoms as with a total lack of the respective proteins.”

With this experiment, the MDC and FMP researchers were able to show for the first time that not only the lack of endosomal/lysosomal acidification, but also a reduced accumulation of chloride ions in these organelles plays a crucial role in generating the severe symptoms of these hereditary diseases, that is a form of kidney stone disease as well as neurodegeneration. A dysregulation of organellar chloride concentration may also play a role in other human diseases.

*Science 11 June 2010, Vol. 328. no. 5984, pp. 1398-1401; DOI: 10.1126/science.1188070; originally published in Science Express on 29 April 2010
*Endosomal Chloride-Proton Exchange Rather Than Chloride Conductance is Crucial for Renal Endocytosis
Gaia Novarino1, Stefanie Weinert1, Gesa Rickheit1,2 & Thomas J. Jentsch1
1 Leibniz-Institut für Molekulare Pharmakologie (FMP)and Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, Germany

2 Present address: TaconicArtemis GmbH, Köln, Germany

Science 11 June 2010, Vol. 328. no. 5984, pp. 1401-1403, DOI: 10.1126/science.1188072; originally published in Science Express on 29 April 2010; * Lysosomal Pathology and Osteopetrosis Upon Loss of H+-Driven Lysosomal Cl- Accumulation
Stefanie Weinert1,2, Sabrina Jabs1,2,6, Chayarop Supanchart3, Michaela Schweizer4, Niclas Gimber1,2, Martin Richter1,6, Jörg Rademann1,6,7, Tobias Stauber1,2,Uwe Kornak3,5 & Thomas J. Jentsch1,2
1 Leibniz-Institut für Molekulare Pharmakologie (FMP), Berlin, Germany
2 Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, Germany
3 Institut für Medizinische Genetik, Charité Universitätsmedizin Berlin, Germany
4 Zentrum für Molekulare Neurobiologie (ZMNH), Universität Hamburg, Hamburg, Germany
5 Max-Planck-Institut für Molekulare Genetik, Berlin, Germany
6 Freie Universität, Berlin, Germany
7Present address: Institut für Pharmazie, Universität Leipzig, Leipzig, Germany
Barbara Bachtler
Press and Public Affairs
Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch
Robert-Rössle-Straße 10; 13125 Berlin; Germany
Phone: +49 (0) 30 94 06 - 38 96
Fax: +49 (0) 30 94 06 - 38 33
e-mail: presse@mdc-berlin.de

Barbara Bachtler | Max-Delbrück-Centrum
Further information:
http://www.mdc-berlin.de/

More articles from Life Sciences:

nachricht Cnidarians remotely control bacteria
21.09.2017 | Christian-Albrechts-Universität zu Kiel

nachricht Immune cells may heal bleeding brain after strokes
21.09.2017 | NIH/National Institute of Neurological Disorders and Stroke

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Highly precise wiring in the Cerebral Cortex

Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.

The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...

Im Focus: Tiny lasers from a gallery of whispers

New technique promises tunable laser devices

Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...

Im Focus: Ultrafast snapshots of relaxing electrons in solids

Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!

When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...

Im Focus: Quantum Sensors Decipher Magnetic Ordering in a New Semiconducting Material

For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.

Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...

Im Focus: Fast, convenient & standardized: New lab innovation for automated tissue engineering & drug

MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems Holding GmbH about commercial use of a multi-well tissue plate for automated and reliable tissue engineering & drug testing.

MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

“Lasers in Composites Symposium” in Aachen – from Science to Application

19.09.2017 | Event News

I-ESA 2018 – Call for Papers

12.09.2017 | Event News

EMBO at Basel Life, a new conference on current and emerging life science research

06.09.2017 | Event News

 
Latest News

Comet or asteroid? Hubble discovers that a unique object is a binary

21.09.2017 | Physics and Astronomy

Cnidarians remotely control bacteria

21.09.2017 | Life Sciences

Monitoring the heart's mitochondria to predict cardiac arrest?

21.09.2017 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>