The synaptic proteome

Laßek, Melanie; Weingarten, Jens; Volknandt, Walter

doi:10.1007/s00441-014-1943-4

Cited by 37 publications

(25 citation statements)

References 130 publications

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“…One problem with the corresponding molecular analysis is the large number of protein classes and isoforms involved in both processes. Determination of the proteome for synapses and synaptic compartments (Laßek et al 2014, this issue) provide a remarkable detailed picture and emphasize the dimension of the challenge to understand, at the molecular level, not only synaptic function but also development.…”

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confidence: 99%

Deciphering the core instructions of neuronal differentiation

Ernsberger

2014

Cell Tissue Res

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The amazing field of Developmental Neuroscience has provided fascinating insights into mechanisms regulating the generation of a huge array of different neuron populations. The discovery of a large set of growth factors influencing cellular differentiation choices and transcription factors regulating expression of genes specific to progenitor and neuron populations has been instrumental. The analysis has failed, however, to establish a clear idea on the acquisition of the common structural as well as information-propagating and -processing neuronal features during neurogenesis. Moreover, it is not resolved how this is coordinated with the diversification of the distinct neuron populations.Focusing attention on the early developmental expression of shared molecular players involved in formation of the neuronal cytoskeleton, generation of action potentials and regulation of neurotransmitter release has begun to change the field. Together with the recognition of several layers in the coordination of gene expression extending from (1) modification of nuclear and chromatin organization to (2) action of transcription regulator complexes at enhancer and promoter sequences to (3) posttranscriptional regulation by powerful non-coding RNA/protein networks, a comprehensive picture of the route from neural progenitor to neuron takes shape.Fueled by the observation that a limited set of regulators from each of these layers has the potential to drive neuronal differentiation in stem cells or even from unrelated cell types such as fibroblasts, the finding of developmental expression patterns of genes coding for neuronal cytoskeletal and synaptic proteins conserved across vertebrate neuron populations prompts the question for a shared generic differentiation program. Involvement of some of those regulators and expression of certain target genes in sensory receptor and endocrine cell differentiation may define a group of related signalcommunicating cells and further refine the core of a neuronal differentiation program. Comparison to invertebrate neural development demonstrating related functions of orthologous regulators will decipher the evolutionary core instructions on 'how to build a neuron'. The consequences of such a basic comprehension of generic neuronal differentiation for stem cell-derived tissue replacement approaches, as well as the neuro-pathological and neuro-oncological clinic, are of particular interest.The exciting search for the mechanisms governing neuronal development has received additional momentum by the goal to predictably tailor programming and reprogramming routines for cell and tissue replacement techniques. Both basic and applied approaches have uncovered or employed, respectively, regulatory schemes related to the diversification of the enormous variety of neuron classes. In order to generate a specific type of neuron in vitro this procedure has already proven successful. Yet Ninkovic and Götz (2014, this issue) discuss the question whether application of a common principle of neuronal differentia...

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confidence: 99%

Deciphering the core instructions of neuronal differentiation

Ernsberger

2014

Cell Tissue Res

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“…The concerted action of a set of proteins present at the release site governs central functions in synaptic signaling (reviewed in [1,2]). Furthermore, constituents of the presynaptic active zone are targets of numerous potent neurotoxins and vulnerable to neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

“…Due to the refinement of mass spectrometric methods proteomic studies of murine brain-derived synaptosomes, synaptic vesicles, postsynaptic densities, and presynaptic active zones (PAZs) recently provided increasing information on the proteomic composition of chemical synapses and their subcompartments (reviewed in [1]). These synaptic proteomes provide the basis for studying the interactome of the molecular constituents identified (reviewed in [2]). In contrast to the complex dynamics of postsynaptic densities [3,4], the dynamic composition of the PAZs is less well characterized, but now arouses increasing interest as a molecular platform of presynaptic plasticity (reviewed in [1]).…”

Section: Introductionmentioning

confidence: 99%

Regional Specializations of the PAZ Proteomes Derived from Mouse Hippocampus, Olfactory Bulb and Cerebellum

et al. 2015

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Neurotransmitter release as well as structural and functional dynamics at the presynaptic active zone (PAZ) comprising synaptic vesicles attached to the presynaptic plasma membrane are mediated and controlled by its proteinaceous components. Here we describe a novel experimental design to immunopurify the native PAZ-complex from individual mouse brain regions such as olfactory bulb, hippocampus, and cerebellum with high purity that is essential for comparing their proteome composition. Interestingly, quantitative immunodetection demonstrates significant differences in the abundance of prominent calcium-dependent PAZ constituents. Furthermore, we characterized the proteomes of the immunoisolated PAZ derived from the three brain regions by mass spectrometry. The proteomes of the release sites from the respective regions exhibited remarkable differences in the abundance of a large variety of PAZ constituents involved in various functional aspects of the release sites such as calcium homeostasis, synaptic plasticity and neurogenesis. On the one hand, our data support an identical core architecture of the PAZ for all brain regions and, on the other hand, demonstrate that the proteinaceous composition of their presynaptic active zones vary, suggesting that changes in abundance of individual proteins strengthen the ability of the release sites to adapt to specific functional requirements.

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“…They consist of a pre- and postsynapse, which are built from hundreds of proteins (Laßek et al, 2015). While the molecular composition and architecture of pre- and postsynapses has been widely explored (Frank and Grant, 2017; Laßek et al, 2015; Van Vactor and Sigrist, 2017), much less is known, how synaptogenesis is regulated at the level of gene expression. Is there a mechanism that coordinates the expression of functionally related proteins such that they are ready to assemble into higher order structures concomitantly?…”

Section: Introductionmentioning

confidence: 99%

The THO Complex Coordinates Transcripts for Synapse Development and Dopamine Neuron Survival

Maeder

Kim

Liang

et al. 2018

Cell

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Synaptic vesicle and active zone proteins are required for synaptogenesis. The molecular mechanisms for coordinated synthesis of these proteins are not understood. Using forward genetic screens, we identified the conserved THO nuclear export complex (THOC) as an important regulator of presynapse development in C. elegans dopaminergic neurons. In THOC mutants, synaptic messenger RNAs are retained in the nucleus, resulting in dramatic decrease of synaptic protein expression, near complete loss of synapses, and compromised dopamine function. CRE binding protein (CREB) interacts with THOC to mark synaptic transcripts for efficient nuclear export. Deletion of Thoc5, a THOC subunit, in mouse dopaminergic neurons causes severe defects in synapse maintenance and subsequent neuronal death in the substantia nigra compacta. These cellular defects lead to abrogated dopamine release, ataxia, and animal death. Together, our results argue that nuclear export mechanisms can select specific mRNAs and be a rate-limiting step for neuronal differentiation and survival.

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The synaptic proteome

Cited by 37 publications

References 130 publications

Deciphering the core instructions of neuronal differentiation

Deciphering the core instructions of neuronal differentiation

Regional Specializations of the PAZ Proteomes Derived from Mouse Hippocampus, Olfactory Bulb and Cerebellum

The THO Complex Coordinates Transcripts for Synapse Development and Dopamine Neuron Survival

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