Neef, Jakob

[["dc.bibliographiccitation.firstpage","2686"],["dc.bibliographiccitation.issue","21"],["dc.bibliographiccitation.journal","EMBO Journal"],["dc.bibliographiccitation.lastpage","2702"],["dc.bibliographiccitation.volume","34"],["dc.contributor.author","Jung, SangYong"],["dc.contributor.author","Maritzen, Tanja"],["dc.contributor.author","Wichmann, Carolin"],["dc.contributor.author","Jing, Zhizi"],["dc.contributor.author","Neef, Andreas"],["dc.contributor.author","Revelo, Natalia H."],["dc.contributor.author","Al-Moyed, Hanan"],["dc.contributor.author","Meese, Sandra"],["dc.contributor.author","Wojcik, Sonja M."],["dc.contributor.author","Panou, Iliana"],["dc.contributor.author","Bulut, Haydar"],["dc.contributor.author","Schu, Peter"],["dc.contributor.author","Ficner, Ralf"],["dc.contributor.author","Reisinger, Ellen"],["dc.contributor.author","Rizzoli, Silvio"],["dc.contributor.author","Neef, Jakob"],["dc.contributor.author","Strenzke, Nicola"],["dc.contributor.author","Haucke, Volker"],["dc.contributor.author","Moser, Tobias"],["dc.date.accessioned","2017-09-07T11:54:53Z"],["dc.date.available","2017-09-07T11:54:53Z"],["dc.date.issued","2015"],["dc.description.abstract","Active zones (AZs) of inner hair cells (IHCs) indefatigably release hundreds of vesicles per second, requiring each release site to reload vesicles at tens per second. Here, we report that the endocytic adaptor protein 2 (AP-2) is required for release site replenishment and hearing. We show that hair cell-specific disruption of AP-2 slows IHC exocytosis immediately after fusion of the readily releasable pool of vesicles, despite normal abundance of membrane-proximal vesicles and intact endocytic membrane retrieval. Sound-driven postsynaptic spiking was reduced in a use-dependent manner, and the altered interspike interval statistics suggested a slowed reloading of release sites. Sustained strong stimulation led to accumulation of endosome-like vacuoles, fewer clathrin-coated endocytic intermediates, andvesicle depletion of the membrane-distal synaptic ribbon in AP-2-deficient IHCs, indicating a further role of AP-2 in clathrin-dependent vesicle reformation on a timescale of many seconds. Finally, we show that AP-2 sorts its IHC-cargo otoferlin. We propose that binding of AP-2 to otoferlin facilitates replenishment of release sites, for example, via speeding AZ clearance of exocytosed material, in addition to a role of AP-2 in synaptic vesicle reformation."],["dc.identifier.doi","10.15252/embj.201591885"],["dc.identifier.gro","3141791"],["dc.identifier.isi","000364337100008"],["dc.identifier.pmid","26446278"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/1112"],["dc.language.iso","en"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.eissn","1460-2075"],["dc.relation.issn","0261-4189"],["dc.title","Disruption of adaptor protein 2μ (AP‐2μ) in cochlear hair cells impairs vesicle reloading of synaptic release sites and hearing"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","10730"],["dc.bibliographiccitation.issue","34"],["dc.bibliographiccitation.journal","The Journal of neuroscience"],["dc.bibliographiccitation.lastpage","10740"],["dc.bibliographiccitation.volume","29"],["dc.contributor.author","Neef, Jakob"],["dc.contributor.author","Gehrt, Anna"],["dc.contributor.author","Bulankina, Anna V."],["dc.contributor.author","Meyer, Alexander C."],["dc.contributor.author","Riedel, Dietmar"],["dc.contributor.author","Gregg, Ronald G."],["dc.contributor.author","Strenzke, Nicola"],["dc.contributor.author","Moser, Tobias"],["dc.date.accessioned","2017-09-07T11:46:52Z"],["dc.date.available","2017-09-07T11:46:52Z"],["dc.date.issued","2009"],["dc.description.abstract","Hearing relies on Ca2+ influx-triggered exocytosis in cochlear inner hair cells (IHCs). Here we studied the role of the Ca2+ channel subunit Ca-V beta(2) in hearing. Of the Ca-V beta(1-4) mRNAs, IHCs predominantly contained Ca-V beta(2). Hearing was severely impaired in mice lacking Ca-V beta(2) in extracardiac tissues (Ca-V beta(-/-)(2)). This involved deficits in cochlear amplification and sound encoding. Otoacoustic emissions were reduced or absent in Ca-V beta(-/-)(2) mice, which showed strongly elevated auditory thresholds in single neuron recordings and auditory brainstem response measurements. Ca-V beta(-/-)(2) IHCs showed greatly reduced exocytosis (by 68%). This was mostly attributable to a decreased number of membrane-standing Ca(V)1.3 channels. Confocal Ca2+ imaging revealed presynaptic Ca2+ microdomains albeit with much lower amplitudes, indicating synaptic clustering of fewer Ca(V)1.3 channels. The coupling of the remaining Ca2+ influx to IHC exocytosis appeared unaffected. Extracellular recordings of sound-evoked spiking in the cochlear nucleus and auditory nerve revealed reduced spike rates in the Ca-V beta(-/-)(2) mice. Still, sizable onset and adapted spike rates were found during suprathreshold stimulation in Ca-V beta 2(-/-) mice. This indicated that residual synaptic sound encoding occurred, although the number of presynaptic Ca(V)1.3 channels and exocytosis were reduced to one-third. The normal developmental upregulation, clustering, and gating of large-conductance Ca2+ activated potassium channels in IHCs were impaired in the absence of Ca-V beta(2). Moreover, we found the developmental efferent innervation to persist in Ca-V beta(2)-deficient IHCs. In summary, Ca-V beta(2) has an essential role in regulating the abundance and properties of Ca(V)1.3 channels in IHCs and, thereby, is critical for IHC development and synaptic encoding of sound."],["dc.identifier.doi","10.1523/JNEUROSCI.1577-09.2009"],["dc.identifier.gro","3143071"],["dc.identifier.isi","000269317900026"],["dc.identifier.pmid","19710324"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/544"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.publisher","Soc Neuroscience"],["dc.relation.issn","0270-6474"],["dc.title","The Ca2+ Channel Subunit beta 2 Regulates Ca2+ Channel Abundance and Function in Inner Hair Cells and Is Required for Hearing"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","eLife"],["dc.bibliographiccitation.volume","7"],["dc.contributor.author","Jean, Philippe"],["dc.contributor.author","Lopez de la Morena, David"],["dc.contributor.author","Michanski, Susann"],["dc.contributor.author","Jaime Tobón, Lina María"],["dc.contributor.author","Gültas, Mehmet"],["dc.contributor.author","Maxeiner, Stephan"],["dc.contributor.author","Strenzke, Nicola"],["dc.contributor.author","Chakrabarti, Rituparna"],["dc.contributor.author","Picher, Maria Magdalena"],["dc.contributor.author","Neef, Jakob"],["dc.contributor.author","Jung, SangYong"],["dc.contributor.author","Neef, Andreas"],["dc.contributor.author","Wichmann, Carolin"],["dc.contributor.author","Grabner, Chad"],["dc.contributor.author","Moser, Tobias"],["dc.date.accessioned","2020-11-24T10:41:13Z"],["dc.date.available","2020-11-24T10:41:13Z"],["dc.date.issued","2018"],["dc.description.abstract","We studied the role of the synaptic ribbon for sound encoding at the synapses between inner hair cells (IHCs) and spiral ganglion neurons (SGNs) in mice lacking RIBEYE (RBEKO/KO). Electron and immunofluorescence microscopy revealed a lack of synaptic ribbons and an assembly of several small active zones (AZs) at each synaptic contact. Spontaneous and sound-evoked firing rates of SGNs and their compound action potential were reduced, indicating impaired transmission at ribbonless IHC-SGN synapses. The temporal precision of sound encoding was impaired and the recovery of SGN-firing from adaptation indicated slowed synaptic vesicle (SV) replenishment. Activation of Ca2+-channels was shifted to more depolarized potentials and exocytosis was reduced for weak depolarizations. Presynaptic Ca2+-signals showed a broader spread, compatible with the altered Ca2+-channel clustering observed by super-resolution immunofluorescence microscopy. We postulate that RIBEYE disruption is partially compensated by multi-AZ organization. The remaining synaptic deficit indicates ribbon function in SV-replenishment and Ca2+-channel regulation."],["dc.identifier.doi","10.7554/eLife.29275"],["dc.identifier.eissn","2050-084X"],["dc.identifier.pmid","29328020"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/69157"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.relation.issn","2050-084X"],["dc.title","The synaptic ribbon is critical for sound encoding at high rates and with temporal precision"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","ddac267"],["dc.bibliographiccitation.journal","Human Molecular Genetics"],["dc.contributor.author","Chepurwar, Shashank"],["dc.contributor.author","von Loh, Sarah M"],["dc.contributor.author","Wigger, Daniela C"],["dc.contributor.author","Neef, Jakob"],["dc.contributor.author","Frommolt, Peter"],["dc.contributor.author","Beutner, Dirk"],["dc.contributor.author","Lang-Roth, Ruth"],["dc.contributor.author","Kubisch, Christian"],["dc.contributor.author","Strenzke, Nicola"],["dc.contributor.author","Volk, Alexander E"],["dc.date.accessioned","2022-11-01T10:16:56Z"],["dc.date.available","2022-11-01T10:16:56Z"],["dc.date.issued","2022"],["dc.description.abstract","Abstract\n Auditory synaptopathy/neuropathy (AS/AN) is a distinct type of sensorineural hearing loss in which the cochlear sensitivity to sound (i.e. active cochlear amplification by outer hair cells) is preserved whereas sound encoding by inner hair cells and/or auditory nerve fibers is disrupted due to genetic or environmental factors. Autosomal-dominant auditory neuropathy type 2 (AUNA2) was linked either to chromosomal bands 12q24 or 13q34 in a large German family in 2017. By whole genome sequencing, we now detected a 5500 bp deletion in ATP11A on chromosome 13q34 segregating with the phenotype in this family. ATP11A encodes a P-type ATPase that translocates phospholipids from the exoplasmic to the cytoplasmic leaflet of the plasma membrane. The deletion affects both isoforms of ATP11A and activates a cryptic splice site leading to the formation of an alternative last exon. ATP11A carrying the altered C-terminus loses its flippase activity for phosphatidylserine. Atp11a is expressed in fibers and synaptic contacts of the auditory nerve and in the cochlear nucleus in mice and conditional Atp11a knockout mice show a progressive reduction of the spiral ganglion neuron compound action potential, recapitulating the human phenotype of auditory neuropathy. By combining whole genome sequencing, immunohistochemistry, in vitro functional assays and generation of a mouse model, we could thus identify a partial deletion of ATP11A as the genetic cause of AUNA2."],["dc.identifier.doi","10.1093/hmg/ddac267"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/116690"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-605"],["dc.relation.eissn","1460-2083"],["dc.relation.issn","0964-6906"],["dc.title","A mutation in\n ATP11A\n causes autosomal-dominant auditory neuropathy type 2"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]