scholarly journals Mutations in Membrin/GOSR2 reveal stringent secretory pathway demands of dendritic growth and synaptic integrity

2017 ◽  
Author(s):  
Roman Praschberger ◽  
Simon A. Lowe ◽  
Nancy T. Malintan ◽  
Henry Houlden ◽  
Dimitri M. Kullmann ◽  
...  
Keyword(s):  
Nervous System ◽  
Membrane Fusion ◽  
Dendritic Growth ◽  
Secretory Pathway ◽  
Synaptic Function ◽  
Golgi Membrane ◽  
Snare Protein ◽  
Progressive Myoclonus Epilepsy ◽  
Myoclonus Epilepsy ◽  
Axonal Trafficking

AbstractMutations in the Golgi SNARE protein Membrin (encoded by the GOSR2 gene) cause progressive myoclonus epilepsy (PME). Membrin is a ubiquitously important protein mediating ER-to-Golgi membrane fusion, and hence it is unclear how these mutations result in a disorder restricted to the nervous system. Here we use a multi-layered strategy to elucidate the consequences of Membrin mutations from protein to neuron. We show that the pathogenic mutations cause partial reductions in SNARE-mediated membrane fusion. Importantly, these alterations were sufficient to profoundly impair dendritic growth in novel Drosophila models of GOSR2-PME. We also observed axonal trafficking abnormalities in this model, as well as synaptic malformations, trans-synaptic instability and hyperactive synaptic transmission. Our study highlights how dendritic growth is vulnerable even to subtle secretory pathway deficits, uncovers a previously uncharacterized role for Membrin in synaptic function, and provides a comprehensive explanatory basis for genotype-phenotype relationships in GOSR2-PME.

scholarly journals Analysis of Sec22p in Endoplasmic Reticulum/Golgi Transport Reveals Cellular Redundancy in SNARE Protein Function

2002 ◽  
Vol 13 (9) ◽  
pp. 3314-3324 ◽  
Author(s):  
Yiting Liu ◽  
Charles Barlowe
Keyword(s):  
Endoplasmic Reticulum ◽  
Membrane Fusion ◽  
Protein Function ◽  
Secretory Pathway ◽  
Snare Proteins ◽  
Snare Protein ◽  
Intracellular Membrane ◽  
Protein Receptor ◽  
Intracellular Membrane Fusion

Membrane-bound soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins form heteromeric complexes that are required for intracellular membrane fusion and are proposed to encode compartmental specificity. In yeast, the R-SNARE protein Sec22p acts in transport between the endoplasmic reticulum (ER) and Golgi compartments but is not essential for cell growth. Other SNARE proteins that function in association with Sec22p (i.e., Sed5p, Bos1p, and Bet1p) are essential, leading us to question how transport through the early secretory pathway is sustained in the absence of Sec22p. In wild-type strains, we show that Sec22p is directly required for fusion of ER-derived vesicles with Golgi acceptor membranes. Insec22Δ strains, Ykt6p, a related R-SNARE protein that operates in later stages of the secretory pathway, is up-regulated and functionally substitutes for Sec22p. In vivo combination of thesec22Δ mutation with a conditionalykt6-1 allele results in lethality, consistent with a redundant mechanism. Our data indicate that the requirements for specific SNARE proteins in intracellular membrane fusion are less stringent than appreciated and suggest that combinatorial mechanisms using both upstream-targeting elements and SNARE proteins are required to maintain an essential level of compartmental organization.

Postsynaptic neuronal geometry and synaptic effectiveness

1987 ◽  
Vol 45 ◽  
pp. 690-697
Author(s):  
C.J. Wilson
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Synaptic Function ◽  
Postsynaptic Neuron ◽  
Synaptic Inputs ◽  
Partial Analysis ◽  
Postsynaptic Cell ◽  
Neuronal Geometry ◽  
The Relationship ◽  
Complex Scale

Most central nervous system neurons receive synaptic input from hundreds or thousands of other neurons, and the computational function of such neurons results from the interactions of inputs on a large and complex scale. In most situations that have yielded to a partial analysis, the synaptic inputs to a neuron are not alike in function, but rather belong to distinct categories that differ qualitatively in the nature of their effect on the postsynaptic cell, and quantitatively in the strength of their influence. Many factors have been demonstrated to contribute to synaptic function, but one of the simplest and best known of these is the geometry of the postsynaptic neuron. The fundamental nature of the relationship between neuronal shape and synaptic effectiveness was established on theoretical grounds prior to its experimental verification.

Glial Cells in the Auditory Brainstem

2018 ◽  
pp. 680-706
Author(s):  
Giedre Milinkeviciute ◽  
Karina S. Cramer
Keyword(s):  
Nervous System ◽  
Glial Cells ◽  
Sound Localization ◽  
Auditory Brainstem ◽  
Synaptic Function ◽  
System Function ◽  
Auditory Neurons ◽  
System P ◽  
The Central Nervous System ◽  
Nervous System Function

The auditory brainstem carries out sound localization functions that require an extraordinary degree of precision. While many of the specializations needed for these functions reside in auditory neurons, additional adaptations are made possible by the functions of glial cells. Astrocytes, once thought to have mainly a supporting role in nervous system function, are now known to participate in synaptic function. In the auditory brainstem, they contribute to development of specialized synapses and to mature synaptic function. Oligodendrocytes play critical roles in regulating timing in sound localization circuitry. Microglia enter the central nervous system early in development, and also have important functions in the auditory system’s response to injury. This chapter highlights the unique functions of these non-neuronal cells in the auditory system.

scholarly journals Altered Expression of Peroxiredoxins in Mouse Model of Progressive Myoclonus Epilepsy upon LPS-Induced Neuroinflammation

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 357
Author(s):  
Mojca Trstenjak Prebanda ◽  
Petra Matjan-Štefin ◽  
Boris Turk ◽  
Nataša Kopitar-Jerala
Keyword(s):  
Mouse Model ◽  
Redox Homeostasis ◽  
Underlying Mechanism ◽  
Loss Of Function ◽  
Altered Expression ◽  
Lps Challenge ◽  
Progressive Myoclonus Epilepsy ◽  
Myoclonus Epilepsy ◽  
The Brain ◽  
Deficient Mice

Stefin B (cystatin B) is an inhibitor of endo-lysosomal cysteine cathepsin, and the loss-of-function mutations in the stefin B gene were reported in patients with Unverricht–Lundborg disease (EPM1), a form of progressive myoclonus epilepsy. Stefin B-deficient mice, a mouse model of the disease, display key features of EPM1, including myoclonic seizures. Although the underlying mechanism is not yet completely clear, it was reported that the impaired redox homeostasis and inflammation in the brain contribute to the progression of the disease. In the present study, we investigated if lipopolysaccharide (LPS)-triggered neuroinflammation affected the protein levels of redox-sensitive proteins: thioredoxin (Trx1), thioredoxin reductase (TrxR), peroxiredoxins (Prxs) in brain and cerebella of stefin B-deficient mice. LPS challenge was found to result in a marked elevation of Trx1 and TrxR in the brain and cerebella of stefin B deficient mice, while Prx1 was upregulated only in cerebella after LPS challenge. Mitochondrial peroxiredoxin 3 (Prx3), was upregulated also in the cerebellar tissue lysates prepared from unchallenged stefin B deficient mice, while after LPS challenge Prx3 was upregulated in stefin B deficient brain and cerebella. Our results imply the role of oxidative stress in the progression of the disease.

scholarly journals Membrane fusion mediated by peptidic SNARE protein analogues: Evaluation of FRET‐based bulk leaflet mixing assays

2021 ◽  
Author(s):  
Barbara E. Hubrich ◽  
Jan‐Dirk Wehland ◽  
Mike C. Groth ◽  
Anastasiya Schirmacher ◽  
Raphael Hubrich ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Snare Protein
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