Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Indefatigable Hearing

09.10.2015

A molecular clearance mechanism enables synapses to continously release Transmitter. Auditory neuroscientists discover bottleneck of information flow in the ear and pave the way for gene therapy of deafness. Publication in „EMBO Journal“

Disabling hearing impairment (HI) affects 360 million people worldwide, and prevalence increases with age. So far, no causal treatment is available for its most common form, sensorineural HI. Göttingen and Berlin scientists have achieved a major advance in our understanding of hearing as well as an important step towards developing gene therapy of deafness.


Figure 1: Active zone clearance

After fusion of synaptic vesicles (red spheres) with the plasma membrane, interaction of AP-2 and otoferlin along opposing protein gradients is hypothesized to enable efficient clearance of exocytosed proteolipid from the release site. Copyright: Jung et al., EMBO J 2015


Figure 2: Deafness of AP-2µ mice and restoration of hearing by gene therapy

Transgenic mice lacking AP-2µ in their hair cells are hearing impaired (red). Hearing was restored by virus-mediated gene therapy (blue). Copyright: Tobias Moser, Institute for Auditory Neuroscience, UMG

Their study showed that the endocytic adaptor protein 2µ is required for hearing by fueling vesicle reloading of the release site for indefatigable synaptic transmission. Without AP-2, which inter-acts with the deafness protein otoferlin, a kind of traffic jam occurs at the release sites, suggesting that AP-2 and Otoferlin teamwork in clearing exocytosed material from the release site. Using virus-mediated transfer of the intact AP-2µ DNA into sensory inner hair cells, the scientist could restore normal synaptic function and hearing.

The research was performed by scientists of several research institutions at the Göttingen Campus within the collaborative research center 889 (CRC) “Cellular Mechanisms of Sensory Processing” and by scientists of the Berlin Leibniz-Institute for Molecular Pharmacology. The work was published in the EMBO Journal.

... more about:
»gene therapy »hair cells »protein »traffic jam

Publication
Sangyong Jung#, Tanja Maritzen#, Carolin Wichmann#, Zhizi Jing, Andreas Neef§, Natalia H. Revelo, Hanan Al-Moyed, Sandra Meese, Sonja M. Wojcik, Iliana Panou, Haydar Bulut, Peter Schu, Ralf Ficner, Ellen Reisinger, Silvio O. Rizzoli, Jakob Neef, Nicola Strenzke, Volker Haucke§ and Tobias Moser§ (2015). Disruption of adaptor protein 2μ (AP-2μ) in cochlear hair cells impairs vesicle reloading of synaptic release sites and hearing. EMBO Journal, DOI: 10.15252/embj.201591885, online: Oct 7th, 2015
# gleichwertiger Beitrag zum Artikel
§ korrespondierender Autor

Specialized contact points between sensory hair cells and auditory nerve cells, the socalled “ribbon” synapses, convert acoustic information into a neural code in the inner ear. The rate of synaptic transmission amounts to amazing hundreds per second, requiring a highly efficient and indefatigable recruitment, fusion and recycling of synaptic vesicles at the active zones of transmitter release. This extraordinary performance involves Otoferlin that is defective in sensorineural deafness. However, the underlying interactions of Otoferlin with other proteins of the synapse are not well understood.

Ultrafast replenishment of release sites requires their efficient clearance after fusion
What limits the rate of transmission at the hair cell synapse? How does Otoferlin enable indefatigable transmitter release? Each of the sub-micrometer-sized active zones likely can relase up to approximately 1000 transmitter-filled synaptic vesicles per second. Such high traffic volume causes loads of vesicular proteins and lipid to strand in the membrane of the active zone. It seems that the synapse employs dedicated mechanisms to clear this stranded material from the fusion zone to the clearance zone from which it will be recycled by endocytosis (re-uptake into the cell). Efficient “active zone clearance” is likely important for ultrafast reloading of the release sites (Figure 1). How this works, so far, was unclear.

Using transgenic mouse lines generated in Berlin and Göttingen, scientists now discovered that the adaptor protein AP-2µ, a crucial component of the endocytic machinery, plays an important role in active zone clearance. Mice are deaf when their hair cells lack AP-2µ (Figure 2). Deafness results from slowed vesicle reloading at the release sites of the active zones, as demonstrated by a multidisciplinary approach.

Dr. Carolin Wichmann, group leader at the Institute for Auditory Neuroscience of the University Medical Center Göttingen and one of the first authors, says: „We were surprised, that transmitter release slowed down already at 20 thousandth of a second of stimulation. Previously, AP-2 was reported to primarily work in the slower process of vesicle recycling.“ In order to understand the underlying molecular mechanism, the scientists also studied the interactions of AP-2 and found binding to Otoferlin, a molecule that is defect in human deafness, which also supports vesicle replenishment at the active zone.

Dr. Tanja Maritzen, group leader at the Leibniz-Institute for Molecular Pharmacology, Berlin, and a first author says: „We found AP-2 and Otoferlin to interact at least via two binding sites. Moreover, our experiments revealed that AP-2µ is critical for maintaining normal levels of Otoferlin.“

But how can the interaction of AP-2 and Otoferlin speed vesicle replenishment at the active zone? Dr. Andreas Neef, group leader at the Göttingen Bernstein Center for Computational Neuroscience and MPI for Dynamics and Self-Organisation, a corresponding author states: „Based on combining systems physiological recordings of transmitter release at single active zone, a unique opportunity at these synapses, with mathematical modeling, we postulate that AP-2 speeds clearance of active zones via binding to Otoferlin.“ Thereby, the scientists believe, exocytosed material can be removed more quickly enabling new vesicles to come in and prepare for the next round of transmitter release (Figure 2). Lack of AP-2 or Otoferlin would then cause a “traffic jam” and impair sound encoding: deafness results.

This study is one of the first world-wide that demonstrates the feasibility of using non-pathogenic virus for gene-replacement therapy in animal models. Dr. SangYong Jung, scientist at the Institute for Auditory Neuroscience of the University Medical Center Göttingen and one of the first authors says: „When injecting adeno-associated virus carrying the DNA for AP-2µ into the cochlea of these deaf mice, we could restore the function of the hair cell synapses and hearing.“

The leaders of the study Dr. Volker Haucke (Director of the Leibniz-Institute for Molecular Pharmacology and Professor at the Free University of Berlin) and Dr. Tobias Moser (Director of Institute for Auditory Neuroscience at the University Medical Center Göttingen and Max-Planck-Fellow at the MPIs for Biophysical Chemistry and Experimental Medicine) agree that this study offers an important advance of our understanding of the function of AP-2 in synaptic transmission and, at the same time, paves the way for future gene therapy of deafness.

Haucke: “The high-throughput performance of the auditory system allowed us to better understand the function of AP-2 at the active zone. AP-2 and Otoferlin seem to teamwork in “active zone clearance” in order to realize the spectacular rates of transmission required for hearing”. Moser adds: „While so far we don’t know of a human deafness caused by mutations in AP-2, our study raises hopes that virus-mediated gene therapy can be translated into the clinic in the near future. The near normal hearing after gene therapy of one ear and the lack of virus spread (e.g. to the other ear) indicate that early intervention could restore hearing in select genetic deafness.”


Further information:
Dr. Carolin Wichmann, Dr. SangYong Jung, Prof. Dr. Tobias Moser
Institute for Auditory Neuroscience and InnerEarLab,
University Medical Center, Georg-August-Universität

Dr. Carolin Wichmann
Arbeitsgruppe Molekulare Architektur von Synapsen
Telefon +49 551 / 39-22604, carolin.wichmann@med.uni-goettingen.de

Dr. SangYong Jung, Prof. Dr. Tobias Moser
Institute for Auditory Neuroscience and InnerEarLab
Telefon +49 551 / 39-22803, tmoser@gwdg.de

Dr. Tanja Maritzen, Prof. Dr. Volker Haucke
Leibniz-Institut für Molekulare Pharmakologie(FMP)
Telefon +49-30-94793101, HAUCKE@fmp-berlin.de

Stefan Weller | idw - Informationsdienst Wissenschaft

Further reports about: gene therapy hair cells protein traffic jam

More articles from Life Sciences:

nachricht Researchers uncover protein-based “cancer signature”
05.12.2016 | Universität Basel

nachricht The Nagoya Protocol Creates Disadvantages for Many Countries when Applied to Microorganisms
05.12.2016 | Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

Im Focus: Molecules change shape when wet

Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water

In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

NASA's AIM observes early noctilucent ice clouds over Antarctica

05.12.2016 | Earth Sciences

Shape matters when light meets atom

05.12.2016 | Physics and Astronomy

Researchers uncover protein-based “cancer signature”

05.12.2016 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>