scholarly journals Cofilin and Actin Dynamics: Multiple Modes of Regulation and Their Impacts in Neuronal Development and Degeneration

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2726
Author(s):  
James R. Bamburg ◽  
Laurie S. Minamide ◽  
O’Neil Wiggan ◽  
Lubna H. Tahtamouni ◽  
Thomas B. Kuhn
Keyword(s):  
Cortical Neurons ◽  
Hippocampal Neurons ◽  
Translational Regulation ◽  
Neuronal Development ◽  
Mitochondrial Fission ◽  
Amyloid Β ◽  
Cellular Prion Protein ◽  
Actin Dynamics ◽  
Specific Regulation ◽  
And Function

Proteins of the actin depolymerizing factor (ADF)/cofilin family are ubiquitous among eukaryotes and are essential regulators of actin dynamics and function. Mammalian neurons express cofilin-1 as the major isoform, but ADF and cofilin-2 are also expressed. All isoforms bind preferentially and cooperatively along ADP-subunits in F-actin, affecting the filament helical rotation, and when either alone or when enhanced by other proteins, promotes filament severing and subunit turnover. Although self-regulating cofilin-mediated actin dynamics can drive motility without post-translational regulation, cells utilize many mechanisms to locally control cofilin, including cooperation/competition with other proteins. Newly identified post-translational modifications function with or are independent from the well-established phosphorylation of serine 3 and provide unexplored avenues for isoform specific regulation. Cofilin modulates actin transport and function in the nucleus as well as actin organization associated with mitochondrial fission and mitophagy. Under neuronal stress conditions, cofilin-saturated F-actin fragments can undergo oxidative cross-linking and bundle together to form cofilin-actin rods. Rods form in abundance within neurons around brain ischemic lesions and can be rapidly induced in neurites of most hippocampal and cortical neurons through energy depletion or glutamate-induced excitotoxicity. In ~20% of rodent hippocampal neurons, rods form more slowly in a receptor-mediated process triggered by factors intimately connected to disease-related dementias, e.g., amyloid-β in Alzheimer’s disease. This rod-inducing pathway requires a cellular prion protein, NADPH oxidase, and G-protein coupled receptors, e.g., CXCR4 and CCR5. Here, we will review many aspects of cofilin regulation and its contribution to synaptic loss and pathology of neurodegenerative diseases.

scholarly journals Sonic hedgehog pathway activation increases mitochondrial abundance and activity in hippocampal neurons

2017 ◽  
Vol 28 (3) ◽  
pp. 387-395 ◽  
Author(s):  
Pamela J. Yao ◽  
Uri Manor ◽  
Ronald S. Petralia ◽  
Rebecca D. Brose ◽  
Ryan T. Y. Wu ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Hippocampal Neurons ◽  
Mitochondrial Fission ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Shh Signaling ◽  
Shh Pathway ◽  
Pathway Activation ◽  
Peptide Hydrogen ◽  
And Function

Mitochondria are essential organelles whose biogenesis, structure, and function are regulated by many signaling pathways. We present evidence that, in hippocampal neurons, activation of the Sonic hedgehog (Shh) signaling pathway affects multiple aspects of mitochondria. Mitochondrial mass was increased significantly in neurons treated with Shh. Using biochemical and fluorescence imaging analyses, we show that Shh signaling activity reduces mitochondrial fission and promotes mitochondrial elongation, at least in part, via suppression of the mitochondrial fission protein dynamin-like GTPase Drp1. Mitochondria from Shh-treated neurons were more electron-dense, as revealed by electron microscopy, and had higher membrane potential and respiratory activity. We further show that Shh protects neurons against a variety of stresses, including the mitochondrial poison rotenone, amyloid β-peptide, hydrogen peroxide, and high levels of glutamate. Collectively our data suggest a link between Shh pathway activity and the physiological properties of mitochondria in hippocampal neurons.

scholarly journals hnRNP-Q1 represses nascent axon growth in cortical neurons by inhibitingGap-43mRNA translation

2016 ◽  
Vol 27 (3) ◽  
pp. 518-534 ◽  
Author(s):  
Kathryn R. Williams ◽  
Damian S. McAninch ◽  
Snezana Stefanovic ◽  
Lei Xing ◽  
Megan Allen ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Posttranscriptional Regulation ◽  
Neuronal Development ◽  
Regulation Of Gene Expression ◽  
Axon Growth ◽  
Mrna Translation ◽  
Actin Dynamics ◽  
Neuro2a Cell ◽  
And Function ◽  
Mrna Binding

Posttranscriptional regulation of gene expression by mRNA-binding proteins is critical for neuronal development and function. hnRNP-Q1 is an mRNA-binding protein that regulates mRNA processing events, including translational repression. hnRNP-Q1 is highly expressed in brain tissue, suggesting a function in regulating genes critical for neuronal development. In this study, we have identified Growth-associated protein 43 (Gap-43) mRNA as a novel target of hnRNP-Q1 and have demonstrated that hnRNP-Q1 represses Gap-43 mRNA translation and consequently GAP-43 function. GAP-43 is a neuronal protein that regulates actin dynamics in growth cones and facilitates axonal growth. Previous studies have identified factors that regulate Gap-43 mRNA stability and localization, but it remains unclear whether Gap-43 mRNA translation is also regulated. Our results reveal that hnRNP-Q1 knockdown increased nascent axon length, total neurite length, and neurite number in mouse embryonic cortical neurons and enhanced Neuro2a cell process extension; these phenotypes were rescued by GAP-43 knockdown. Additionally, we have identified a G-quadruplex structure in the 5′ untranslated region of Gap-43 mRNA that directly interacts with hnRNP-Q1 as a means to inhibit Gap-43 mRNA translation. Therefore hnRNP-Q1–mediated repression of Gap-43 mRNA translation provides an additional mechanism for regulating GAP-43 expression and function and may be critical for neuronal development.

FKBP51 Modulates Hippocampal Size and Function in Post-translational Regulation of Parkin

2021 ◽  
Author(s):  
Bin Qiu ◽  
Zhaohui Zhong ◽  
Shawn Righter ◽  
Yuxue Xu ◽  
Jun Wang ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Translational Regulation ◽  
Disease Onset ◽  
Fold Increase ◽  
Knock Out ◽  
Fk506 Binding Protein ◽  
Protein Levels ◽  
And Function

Abstract FK506-binding protein 51 (encoded by Fkpb51) has been associated with stress-related mental illness. To identify its function, we studied the morphological consequences of Fkbp51 deletion. Artificial Intelligence-assist morphological analysis identified that Fkbp51 knock-out (KO) mice possess more elongated CA and DG but shorter in height in coronal section when compared to WT. Primary cultured Fkbp51 KO hippocampal neurons were shown to exhibit larger dendritic outgrowth than wild-type (WT) controls, pharmacological manipulation experiments suggest that this may occur through regulation of microtubule-associated protein. Both in vitro primary culture and in vivo labeling support that FKBP51 regulates microtubule-associated protein expression. Furthermore, in the absence of differences in mRNA expression, Fkbp51 KO hippocampus exhibited decreases in βIII-tubulin, MAP2, and Tau protein levels, but a greater than 2.5-fold increase in Parkin protein. Overexpression and knock-down FKBP51 demonstrated that FKBP51 negatively regulates Parkin in a dose-dependent and ubiquitin-mediated manner. These results indicate a potential novel post-translational regulatory of Parkin by FKBP51 and significance of their interaction on disease onset.

scholarly journals Neurotrophic Effect of Fish-Lecithin Based Nanoliposomes on Cortical Neurons

Marine Drugs ◽  
2019 ◽  
Vol 17 (7) ◽  
pp. 406 ◽  
Author(s):  
Catherine Malaplate ◽  
Aurelia Poerio ◽  
Marion Huguet ◽  
Claire Soligot ◽  
Elodie Passeri ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Cortical Neurons ◽  
Neuronal Development ◽  
Synapse Formation ◽  
Fatty Acid Content ◽  
Primary Cultures ◽  
Synaptic Membrane ◽  
Neuronal Membranes ◽  
Acid Ratio ◽  
And Function

Lipids play multiple roles in preserving neuronal function and synaptic plasticity, and polyunsaturated fatty acids (PUFAs) have been of particular interest in optimizing synaptic membrane organization and function. We developed a green-based methodology to prepare nanoliposomes (NL) from lecithin that was extracted from fish head by-products. These NL range between 100–120 nm in diameter, with an n-3/n-6 fatty acid ratio of 8.88. The high content of n-3 PUFA (46.3% of total fatty acid content) and docosahexanoic acid (26%) in these NL represented a means for enrichment of neuronal membranes that are potentially beneficial for neuronal growth and synaptogenesis. To test this, the primary cultures of rat embryo cortical neurons were incubated with NL on day 3 post-culture for 24 h, followed by immunoblots or immunofluorescence to evaluate the NL effects on synaptogenesis, axonal growth, and dendrite formation. The results revealed that NL-treated cells displayed a level of neurite outgrowth and arborization on day 4 that was similar to those of untreated cells on day 5 and 6, suggesting accelerated synapse formation and neuronal development in the presence of NL. We propose that fish-derived NL, by virtue of their n-3 PUFA profile and neurotrophic effects, represent a new innovative bioactive vector for developing preventive or curative treatments for neurodegenerative diseases.

scholarly journals The TRIM9/TRIM67 neuronal interactome reveals novel activators of morphogenesis

2020 ◽  
Author(s):  
Shalini Menon ◽  
Dennis Goldfarb ◽  
Tsungyo Ho ◽  
Erica W. Cloer ◽  
Nicholas P. Boyer ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Hippocampal Neurons ◽  
Spatial Learning And Memory ◽  
Dependent Manner ◽  
Synaptic Regulation ◽  
Form And Function ◽  
Guidance Cue ◽  
And Function ◽  
Trim Proteins ◽  
Protein Transporters

ABSTRACTTRIM9 and TRIM67 are neuronally-enriched E3 ubiquitin ligases essential for appropriate morphogenesis of cortical and hippocampal neurons and fidelitous responses to the axon guidance cue netrin-1. Deletion of murine Trim9 or Trim67 results in neuroanatomical defects and striking behavioral deficits, particularly in spatial learning and memory. TRIM9 and TRIM67 interact with cytoskeletal and exocytic proteins, but the full interactome is not known. Here we performed the unbiased proximity-dependent biotin identification (BioID) approach to define TRIM9 and TRIM67 protein-protein proximity network in developing cortical neurons and identified neuronal putative TRIM interaction partners. Candidates included cytoskeletal regulators, cytosolic protein transporters, exocytosis and endocytosis regulators, and proteins necessary for synaptic regulation. A subset of high priority candidates was validated, including Myo16, Coro1A, SNAP47, ExoC1, GRIP1, PRG-1, and KIF1A. For a subset of validated candidates, we utilized TIRF microscopy to demonstrate dynamic colocalization with TRIM proteins at the axonal periphery, including at the tips of filopodia. Further analysis demonstrated the RNAi-based knockdown of the unconventional myosin Myo16 in cortical neurons altered axonal branching patterns in a TRIM9 and netrin-1 dependent manner. Future analysis of other validated candidates will likely identify novel proteins and mechanisms by which TRIM9 and TRIM67 regulate neuronal form and function.

scholarly journals Interaction of amyloid-β (Aβ) oligomers with neurexin 2α and neuroligin 1 mediates synapse damage and memory loss in mice

2017 ◽  
Vol 292 (18) ◽  
pp. 7327-7337 ◽  
Author(s):  
Jordano Brito-Moreira ◽  
Mychael V. Lourenco ◽  
Mauricio M. Oliveira ◽  
Felipe C. Ribeiro ◽  
José Henrique Ledo ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Memory Impairment ◽  
Memory Loss ◽  
Amyloid Β ◽  
Structure Stability ◽  
Amyloid Β Protein ◽  
Aβ Oligomers ◽  
Synapse Loss ◽  
Synaptic Interactions ◽  
And Function

Brain accumulation of the amyloid-β protein (Aβ) and synapse loss are neuropathological hallmarks of Alzheimer disease (AD). Aβ oligomers (AβOs) are synaptotoxins that build up in the brains of patients and are thought to contribute to memory impairment in AD. Thus, identification of novel synaptic components that are targeted by AβOs may contribute to the elucidation of disease-relevant mechanisms. Trans-synaptic interactions between neurexins (Nrxs) and neuroligins (NLs) are essential for synapse structure, stability, and function, and reduced NL levels have been associated recently with AD. Here we investigated whether the interaction of AβOs with Nrxs or NLs mediates synapse damage and cognitive impairment in AD models. We found that AβOs interact with different isoforms of Nrx and NL, including Nrx2α and NL1. Anti-Nrx2α and anti-NL1 antibodies reduced AβO binding to hippocampal neurons and prevented AβO-induced neuronal oxidative stress and synapse loss. Anti-Nrx2α and anti-NL1 antibodies further blocked memory impairment induced by AβOs in mice. The results indicate that Nrx2α and NL1 are targets of AβOs and that prevention of this interaction reduces the deleterious impact of AβOs on synapses and cognition. Identification of Nrx2α and NL1 as synaptic components that interact with AβOs may pave the way for development of novel approaches aimed at halting synapse failure and cognitive loss in AD.

scholarly journals c-Jun NH2-terminal Kinase (JNK)-interacting Protein-3 (JIP3) Regulates Neuronal Axon Elongation in a Kinesin- and JNK-dependent Manner

2013 ◽  
Vol 288 (20) ◽  
pp. 14531-14543 ◽  
Author(s):  
Tao Sun ◽  
Nuo Yu ◽  
Lu-Kai Zhai ◽  
Na Li ◽  
Chao Zhang ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Hippocampal Neurons ◽  
Molecular Mechanisms ◽  
Neuronal Development ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Anterograde Transport ◽  
Interacting Protein ◽  
Axon Elongation

The development of neuronal polarity is essential for the establishment of the accurate patterning of neuronal circuits in the brain. However, little is known about the underlying molecular mechanisms that control rapid axon elongation during neuronal development. Here, we report that c-Jun NH2-terminal kinase (JNK)-interacting protein-3 (JIP3) is highly expressed at axon tips during the critical period for axon development. Using gain- and loss-of-function approaches, immunofluorescence analysis, and in utero electroporation, we find that JIP3 can enhance axon elongation in primary hippocampal neurons and cortical neurons in vivo. We further demonstrate that JIP3 promotes axon elongation in a kinesin- and JNK-dependent manner using several deletion mutants of JIP3. Next, we demonstrate that the successful transportation of JIP3 to axon tips by kinesin is a prerequisite for enhancing JNK phosphorylation in this area and therefore promotes axon elongation, constituting a novel mechanism for coupling JIP3 anterograde transport with JNK signaling at the distal axons and axon elongation. Finally, our immunofluorescence data suggest that the activation of JNK at axon tips facilitates axon elongation by modulating cofilin activity and actin filament dynamics. These findings may have important implications for our understanding of neuronal axon elongation during development.

scholarly journals Suppression of DSB Formation by Polβ in Active DNA Demethylation is Required for Postnatal Hippocampal Development

2019 ◽  
Author(s):  
Akiko Uyeda ◽  
Kohei Onishi ◽  
Teruyoshi Hirayama ◽  
Satoko Hattori ◽  
Tsuyoshi Miyakawa ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Hippocampal Neurons ◽  
Genome Stability ◽  
Neuronal Development ◽  
Excision Repair ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Dna Demethylation ◽  
Spatial Learning And Memory ◽  
Active Dna Demethylation

AbstractGenome stability is essential for brain development and function. However, the contribution of DNA repair to genome stability in neurons remains elusive. Here, we demonstrate that the base excision repair protein Polβ is involved in hippocampal neuronal differentiation via a TET-mediated active DNA demethylation during early postnatal stages. Polβ deficiency induced extensive DNA double-strand breaks (DSBs) in hippocampal neurons, and a lesser extent in cortical neurons, during a period in which decreased levels of 5-methylcytosine were observed in genomic DNA. Inhibition of the hydroxylation of 5-methylcytosine by microRNAs miR29a/b-1 expression diminished DSB formation. Conversely, its induction by TET1 overexpression increased DSBs. The damaged hippocampal neurons exhibited aberrant neuronal gene expression profiles and dendrite formation. Behavioral analyses revealed impaired spatial learning and memory in adulthood. Thus, Polβ maintains genome stability in the active DNA demethylation that occurs during postnatal neuronal development, thereby contributing to differentiation and subsequent behavior.

scholarly journals Mitochondrial Structure and Polarity in Dendrites and the Axon Initial Segment Are Regulated by Homeostatic Plasticity and Dysregulated in Fragile X Syndrome

2021 ◽  
Vol 9 ◽  
Author(s):  
Pernille Bülow ◽  
Peter A. Wenner ◽  
Victor Faundez ◽  
Gary J. Bassell
Keyword(s):  
Fragile X Syndrome ◽  
Neurodevelopmental Disorders ◽  
Cortical Neurons ◽  
Initial Segment ◽  
Fragile X ◽  
Axon Initial Segment ◽  
Homeostatic Plasticity ◽  
Mitochondrial Morphology ◽  
Specific Regulation ◽  
And Function

Mitochondrial dysfunction has long been overlooked in neurodevelopmental disorders, but recent studies have provided new links to genetic forms of autism, including Rett syndrome and fragile X syndrome (FXS). Mitochondria show plasticity in morphology and function in response to neuronal activity, and previous research has reported impairments in mitochondrial morphology and function in disease. We and others have previously reported abnormalities in distinct types of homeostatic plasticity in FXS. It remains unknown if or how activity deprivation triggering homeostatic plasticity affects mitochondria in axons and/or dendrites and whether impairments occur in neurodevelopmental disorders. Here, we test the hypothesis that mitochondria are structurally and functionally modified in a compartment-specific manner during homeostatic plasticity using a model of activity deprivation in cortical neurons from wild-type mice and that this plasticity-induced regulation is altered in Fmr1-knockout (KO) neurons. We uncovered dendrite-specific regulation of the mitochondrial surface area, whereas axon initial segment (AIS) mitochondria show changes in polarity; both responses are lost in the Fmr1 KO. Taken together, our results demonstrate impairments in mitochondrial plasticity in FXS, which has not previously been reported. These results suggest that mitochondrial dysregulation in FXS could contribute to abnormal neuronal plasticity, with broader implications to other neurodevelopmental disorders and therapeutic strategies.

scholarly journals Opposing functions of F-BAR proteins in neuronal membrane protrusion, tubule formation, and neurite outgrowth

2019 ◽  
Vol 2 (3) ◽  
pp. e201800288 ◽  
Author(s):  
Kendra L Taylor ◽  
Russell J Taylor ◽  
Karl E Richters ◽  
Brandon Huynh ◽  
Justin Carrington ◽  
...  
Keyword(s):  
Neurite Outgrowth ◽  
Cortical Neurons ◽  
Neuronal Development ◽  
Actin Dynamics ◽  
Neuronal Membrane ◽  
Membrane Protrusion ◽  
Tubule Formation ◽  
Primary Cortical Neurons ◽  
Splice Isoforms ◽  
Neurite Formation

The F-BAR family of proteins play important roles in many cellular processes by regulating both membrane and actin dynamics. The CIP4 family of F-BAR proteins is widely recognized to function in endocytosis by elongating endocytosing vesicles. However, in primary cortical neurons, CIP4 concentrates at the tips of extending lamellipodia and filopodia and inhibits neurite outgrowth. Here, we report that the highly homologous CIP4 family member, FBP17, induces tubular structures in primary cortical neurons and results in precocious neurite formation. Through domain swapping and deletion experiments, we demonstrate that a novel polybasic region between the F-BAR and HR1 domains is required for membrane bending. Moreover, the presence of a poly-PxxP region in longer splice isoforms of CIP4 and FBP17 largely reverses the localization and function of these proteins. Thus, CIP4 and FBP17 function as an antagonistic pair to fine-tune membrane protrusion, endocytosis, and neurite formation during early neuronal development.

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