scholarly journals Recent insights on principles of synaptic protein degradation

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 675 ◽  
Author(s):  
Laurie D. Cohen ◽  
Noam E. Ziv
Keyword(s):  
Protein Degradation ◽  
Life Cycles ◽  
Synaptic Proteins ◽  
Degradation Pathways ◽  
Synaptic Protein ◽  
Turnover Rates ◽  
Complex Life Cycles ◽  
Cellular Context ◽  
Experimental Approaches ◽  
And Function

Maintaining synaptic integrity and function depends on the continuous removal and degradation of aged or damaged proteins. Synaptic protein degradation has received considerable attention in the context of synaptic plasticity and growing interest in relation to neurodegenerative and other disorders. Conversely, less attention has been given to constitutive, ongoing synaptic protein degradation and the roles canonical degradation pathways play in these processes. Here we briefly review recent progress on this topic and new experimental approaches which have expedited such progress and highlight several emerging principles. These include the realization that synaptic proteins typically have unusually long lifetimes, as might be expected from the remote locations of most synaptic sites; the possibility that degradation pathways can change with time from synthesis, cellular context, and physiological input; and that degradation pathways, other than ubiquitin-proteasomal-mediated degradation, might play key roles in constitutive protein degradation at synaptic sites. Finally, we point to the importance of careful experimental design and sufficiently sensitive techniques for studying synaptic protein degradation, which bring into account their slow turnover rates and complex life cycles.

Memory Reorganization by Synaptic Protein Degradation

2009 ◽  
Vol 24 (S1) ◽  
pp. 1-1
Author(s):  
B.-K. Kaang
Keyword(s):  
Protein Synthesis ◽  
Protein Degradation ◽  
Memory Retrieval ◽  
De Novo ◽  
Critical Role ◽  
Contextual Fear Conditioning ◽  
Synaptic Proteins ◽  
Protein Synthesis Inhibitor ◽  
Synaptic Protein

An accumulating body of evidence shows that the retrieval process of long-term memory is not static and requires de novo protein synthesis. Thus long-term memories are dynamic and particularly become fragile during its retrieval. Importantly, memory retrieval is regarded as a step necessary for incorporating new information into preexisting memories. We have examined whether protein degradation is involved in the memory reorganization or not. In this presentation I will present the evidence that synaptic proteins are degraded by polyubiquitination and proteasome pathway in the hippocampus after the retrieval of contextual fear conditioning. In addition, we found that the infusion of a proteasome inhibitor into the hippocampus prevented the memory impairment induced by anisomycin, a protein synthesis inhibitor. This indicates that ubiquitin/proteasome-dependent protein degradation is involved in destabilization processes accompanying the memory retrieval. It also supports our hypothesis that preexisting memory is disrupted by synaptic protein degradation before updated memory is strengthened by protein synthesis. Our data also showed that synaptic protein degradation plays a critical role in fear memory extinction, a simple form of memory reorganization. Taken together, synaptic protein degradation is critically involved in the reorganization of the preexisting memories.

scholarly journals MAP2 is differentially phosphorylated in schizophrenia, altering its function

2021 ◽  
Author(s):  
M. J. Grubisha ◽  
X. Sun ◽  
M. L. MacDonald ◽  
M. Garver ◽  
Z. Sun ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Disease Risk ◽  
Protein Translation ◽  
Synaptic Proteins ◽  
Synaptic Protein ◽  
Spine Density ◽  
Neuronal Structure ◽  
Protein Levels ◽  
And Function

AbstractSchizophrenia (Sz) is a highly polygenic disorder, with common, rare, and structural variants each contributing only a small fraction of overall disease risk. Thus, there is a need to identify downstream points of convergence that can be targeted with therapeutics. Reduction of microtubule-associated protein 2 (MAP2) immunoreactivity (MAP2-IR) is present in individuals with Sz, despite no change in MAP2 protein levels. MAP2 is phosphorylated downstream of multiple receptors and kinases identified as Sz risk genes, altering its immunoreactivity and function. Using an unbiased phosphoproteomics approach, we quantified 18 MAP2 phosphopeptides, 9 of which were significantly altered in Sz subjects. Network analysis grouped MAP2 phosphopeptides into three modules, each with a distinct relationship to dendritic spine loss, synaptic protein levels, and clinical function in Sz subjects. We then investigated the most hyperphosphorylated site in Sz, phosphoserine1782 (pS1782). Computational modeling predicted phosphorylation of S1782 reduces binding of MAP2 to microtubules, which was confirmed experimentally. We generated a transgenic mouse containing a phosphomimetic mutation at S1782 (S1782E) and found reductions in basilar dendritic length and complexity along with reduced spine density. Because only a limited number of MAP2 interacting proteins have been previously identified, we combined co-immunoprecipitation with mass spectrometry to characterize the MAP2 interactome in mouse brain. The MAP2 interactome was enriched for proteins involved in protein translation. These associations were shown to be functional as overexpression of wild type and phosphomimetic MAP2 reduced protein synthesis in vitro. Finally, we found that Sz subjects with low MAP2-IR had reductions in the levels of synaptic proteins relative to nonpsychiatric control (NPC) subjects and to Sz subjects with normal and MAP2-IR, and this same pattern was recapitulated in S1782E mice. These findings suggest a new conceptual framework for Sz—that a large proportion of individuals have a “MAP2opathy”—in which MAP function is altered by phosphorylation, leading to impairments of neuronal structure, synaptic protein synthesis, and function.

scholarly journals MAP2 is Differentially Phosphorylated in Schizophrenia, Altering its Function

2019 ◽  
Author(s):  
MJ Grubisha ◽  
X Sun ◽  
ML MacDonald ◽  
M Garver ◽  
Z Sun ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Disease Risk ◽  
Protein Translation ◽  
Synaptic Proteins ◽  
Synaptic Protein ◽  
Spine Density ◽  
Neuronal Structure ◽  
Protein Levels ◽  
And Function

AbstractSchizophrenia (Sz) is a highly polygenic disorder, with common, rare, and structural variants each contributing only a small fraction of overall disease risk. Thus, there is a need to identify downstream points of convergence that can be targeted with therapeutics. Reduction of Microtubule-associated Protein 2 (MAP2) immunoreactivity (MAP2-IR) is present in individuals with Sz, despite no change in MAP2 protein levels. MAP2 is phosphorylated downstream of multiple receptors and kinases identified as Sz risk genes, altering its immunoreactivity and function. Using an unbiased phosphoproteomics approach we quantified 18 MAP2 phosphopeptides, 9 of which were significantly altered in Sz subjects. Network analysis grouped MAP2 phosphopeptides into 3 modules, each with a distinct relationship to dendritic spine loss, synaptic protein levels, and clinical function in Sz subjects. We then investigated the most hyperphosphorylated site in Sz, phosphoserine1782 (pS1782). Computational modeling predicted phosphorylation of S1782 reduces binding of MAP2 to microtubules, which was confirmed experimentally. We generated a transgenic mouse containing a phosphomimetic mutation at S1782 (S1782E) and found reductions in basilar dendritic length and complexity along with reduced spine density. Because only a limited number of MAP2 interacting proteins have been previously identified, we combined co-immunoprecipitation with mass spectrometry to characterize the MAP2 interactome in mouse brain. The MAP2 interactome was enriched for proteins involved in protein translation. These associations were shown to be functional as overexpression of wildtype and phosphomimetic MAP2 reduced protein synthesis in vitro. Finally, we found that Sz subjects with low MAP2-IR had reductions in the levels of synaptic proteins relative to nonpsychiatric control (NPC) subjects and to Sz subjects with normal and MAP2-IR, and this same pattern was recapitulated in S1782E mice. These findings suggest a new conceptual framework for Sz - that a large proportion of individuals have a “MAP2opathy” - in which MAP function is altered by phosphorylation, leading to impairments of neuronal structure, synaptic protein synthesis, and function.

scholarly journals VAMP-2 is a surrogate cerebrospinal fluid marker of Alzheimer-related cognitive impairment in adults with Down syndrome

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Alberto Lleó ◽  
Maria Carmona-Iragui ◽  
Laura Videla ◽  
Susana Fernández ◽  
Bessy Benejam ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Down Syndrome ◽  
Cognitive Impairment ◽  
Episodic Memory ◽  
Cognitive Performance ◽  
Synaptic Proteins ◽  
Selected Reaction Monitoring ◽  
Synaptic Protein ◽  
Csf Levels ◽  
Syntaxin 1B

Abstract Background There is an urgent need for objective markers of Alzheimer’s disease (AD)-related cognitive impairment in people with Down syndrome (DS) to improve diagnosis, monitor disease progression, and assess response to disease-modifying therapies. Previously, GluA4 and neuronal pentraxin 2 (NPTX2) showed limited potential as cerebrospinal fluid (CSF) markers of cognitive impairment in adults with DS. Here, we compare the CSF profile of a panel of synaptic proteins (Calsyntenin-1, Neuroligin-2, Neurexin-2A, Neurexin-3A, Syntaxin-1B, Thy-1, VAMP-2) to that of NPTX2 and GluA4 in a large cohort of subjects with DS across the preclinical and clinical AD continuum and explore their correlation with cognitive impairment. Methods We quantified the synaptic panel proteins by selected reaction monitoring in CSF from 20 non-trisomic cognitively normal controls (mean age 44) and 80 adults with DS grouped according to clinical AD diagnosis (asymptomatic, prodromal AD or AD dementia). We used regression analyses to determine CSF changes across the AD continuum and explored correlations with age, global cognitive performance (CAMCOG), episodic memory (modified cued-recall test; mCRT) and CSF biomarkers, CSF Aβ42:40 ratio, CSF Aβ1-42, CSF p-tau, and CSF NFL. P values were adjusted for multiple testing. Results In adults with DS, VAMP-2 was the only synaptic protein to correlate with episodic memory (delayed recall adj.p = .04) and age (adj.p = .0008) and was the best correlate of CSF Aβ42:40 (adj.p = .0001), p-tau (adj.p < .0001), and NFL (adj.p < .0001). Compared to controls, mean VAMP-2 levels were lower in asymptomatic adults with DS only (adj.p = .02). CSF levels of Neurexin-3A, Thy-1, Neurexin-2A, Calysntenin-1, Neuroligin-2, GluA4, and Syntaxin-1B all strongly correlated with NPTX2 (p < .0001), which was the only synaptic protein to show reduced CSF levels in DS at all AD stages compared to controls (adj.p < .002). Conclusion These data show proof-of-concept for CSF VAMP-2 as a potential marker of synapse degeneration that correlates with CSF AD and axonal degeneration markers and cognitive performance.

scholarly journals Metabarcoding Malaise traps and soil eDNA reveals seasonal and local arthropod diversity shifts

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ameli Kirse ◽  
Sarah J. Bourlat ◽  
Kathrin Langen ◽  
Vera G. Fonseca
Keyword(s):  
Habitat Preferences ◽  
Life Cycles ◽  
Soil Samples ◽  
Turnover Rates ◽  
Arthropod Diversity ◽  
Arthropod Species ◽  
Species Overlap ◽  
Below Ground ◽  
Phenological Shifts ◽  
Malaise Traps

AbstractForest habitats host enormous diversity, but little is known about the seasonal turnover of arthropod species between the above- and below ground forest layers. In this study, we used metabarcoding approaches to uncover arthropod diversity in different forest types and seasons. Our study shows that metabarcoding soil eDNA and Malaise trap bulk samples can provide valuable insights into the phenology and life cycles of arthropods. We found major differences in arthropod species diversity between soil samples and Malaise traps, with only 11.8% species overlap. Higher diversity levels were found in Malaise traps in summer whereas soil samples showed a diversity peak in winter, highlighting the seasonal habitat preferences and life strategies of arthropods. We conclude that collecting time series of bulk arthropod samples and eDNA in the same locations provides a more complete picture of local arthropod diversity and turnover rates and may provide valuable information on climate induced phenological shifts for long-term monitoring.

scholarly journals Impacts of climate change on the complex life cycles of fish

2012 ◽  
Vol 22 (2) ◽  
pp. 121-139 ◽  
Author(s):  
Pierre Petitgas ◽  
Adriaan D. Rijnsdorp ◽  
Mark Dickey-Collas ◽  
Georg H. Engelhard ◽  
Myron A. Peck ◽  
...  
Keyword(s):  
Climate Change ◽  
Life Cycles ◽  
Complex Life Cycles ◽  
Impacts Of Climate Change

scholarly journals Protein synthesis in the dendrite

2002 ◽  
Vol 357 (1420) ◽  
pp. 521-529 ◽  
Author(s):  
Shao Jun Tang ◽  
Erin M. Schuman
Keyword(s):  
Protein Synthesis ◽  
Neural Plasticity ◽  
Messenger Rna ◽  
Mrna Translation ◽  
Synaptic Activity ◽  
Synaptic Proteins ◽  
Local Source ◽  
Synaptic Protein ◽  
Specific Proteins ◽  
Molecular Nature

In neurons, many proteins that are involved in the transduction of synaptic activity and the expression of neural plasticity are specifically localized at synapses. How these proteins are targeted is not clearly understood. One mechanism is synaptic protein synthesis. According to this idea, messenger RNA (mRNA) translation from the polyribosomes that are observed at the synaptic regions provides a local source of synaptic proteins. Although an increasing number of mRNA species has been detected in the dendrite, information about the synaptic synthesis of specific proteins in a physiological context is still limited. The physiological function of synaptic synthesis of specific proteins in synaptogenesis and neural plasticity expression remains to be shown. Experiments aimed at understanding the mechanisms and functions f synaptic protein synthesis might provide important information about the molecular nature of neural plasticity.

Complex Life Cycles: Why Refrain from Growth before Reproduction in the Adult Niche?

2013 ◽  
Vol 181 (1) ◽  
pp. 39-51 ◽  
Author(s):  
Daniel P. Benesh ◽  
James C. Chubb ◽  
Geoff A. Parker
Keyword(s):  
Life Cycles ◽  
Complex Life Cycles
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