Neuronal Homeostasis Research Articles

Cellular Sources and Neuroprotective Roles of Interleukin-10 in the Facial Motor Nucleus after Axotomy.

Facial motoneuron (FMN) survival is mediated by CD4+ T cells in an interleukin-10 (IL-10)-dependent manner after facial nerve axotomy (FNA), but CD4+ T cells themselves are not the source of this neuroprotective IL-10. The aims of this study were to (1) identify the temporal and cell-specific induction of IL-10 expression in the facial motor nucleus and (2) elucidate the neuroprotective capacity of this expression after axotomy. Immunohistochemistry revealed that FMN constitutively produced IL-10, whereas astrocytes were induced to make IL-10 after FNA. Il10 mRNA co-localized with microglia before and after axotomy, but microglial production of IL-10 protein was not detected. To determine whether any single source of IL-10 was critical for FMN survival, Cre/Lox mouse strains were utilized to selectively knock out IL-10 in neurons, astrocytes, and microglia. In agreement with the localization data reflecting concerted IL-10 production by multiple cell types, no single cellular source of IL-10 alone could provide neuroprotection after FNA. These findings suggest that coordinated neuronal and astrocytic IL-10 production is necessary for FMN survival and has roles in neuronal homeostasis, as well as neuroprotective trophism after axotomy.

Preclinical Model to Evaluate Outcomes of Amyloid Cross-Toxicity in the Rodent Brain.

The progress of neurodegenerative disorders correlates with the spread of their associated amyloidogenic proteins. Here, we investigated whether amyloid entry into nonconstitutive neurons could drive cross-toxic outcomes. Amyloid β (Aβ) was stereotaxically introduced into the rodent midbrain tegmentum, where it is not endogenously expressed. Postinfusion, rodent motor and sensorimotor capacities were assessed by standard behavioral tests at 3, 6, 9, and 12 months. The longitudinal study revealed no behavioral abnormalities. However, Aβ insult provoked intraneuronal inclusions positive for phosphorylated α-synuclein in dopaminergic neurons and were seen throughout the midbrain, a pathognomonic biomarker suggesting Parkinson's pathogenesis. These findings not only underscore the cross-toxic potential of amyloid proteins but also provide a mechanism by which they disrupt homeostasis in nonconstitutive neurons and cause neuronal corruption, injury, and demise. This study may help reconcile the large incidence of neurodegenerative comorbidity observed clinically.

Targeting firing rate neuronal homeostasis can prevent seizures

ABSTRACTManipulating firing-rate neuronal homeostasis, which enables neurons to regulate their intrinsic excitability, offers an attractive opportunity to prevent seizures. However, to date, no drug-based interventions have been reported that manipulate this type of neuronal homeostatic mechanism. Here, we used a combination of Drosophila and mouse, and, in the latter, both a pentylenetetrazole (PTZ)-induced seizure model and an electrically induced seizure model for refractory seizures to evaluate the anticonvulsant efficacy of a novel class of anticonvulsant compounds, based on 4-tert-butyl-benzaldehyde (4-TBB). The mode of action included increased expression of the firing rate homeostatic regulator Pumilio (PUM). Knockdown of pum expression, in Drosophila, blocked anticonvulsive effects of 4-TBB, while analysis of validated PUM targets in mouse brain revealed significant reductions following exposure to this compound. A structure-activity study identified the active parts of the molecule and, further, showed that the pyrazole analogue demonstrates highest efficacy, being active against both PTZ-induced and electrically induced seizures. This study provides a proof of principle that anticonvulsant effects can be achieved through regulation of firing rate neuronal homeostasis and identifies a possible chemical compound for future development.

Reducing the shock factor with new anti-epilepsy drugs

Epilepsy is one of the most common serious neurological conditions, affecting 1 in 131 people in the UK. Patients with epilepsy suffer recurrent spontaneous seizures when neuronal activity elevates beyond physiological limits. Although current anti-epileptic drugs can effectively prevent seizures in some patients, up to 20% of paediatric and 40% of adult patients are refractory to treatment. One therapeutic avenue that has not yet been pursued for epilepsy is targeting neuronal homeostasis. PUMILIO (PUM) is a transcriptional repressor that maintains neuron action potentials within physiological limits and, importantly, is abnormally reduced in patients with epilepsy. In their recent article, Richard Baines and colleagues, therefore, investigated PUM as a therapeutic target for epilepsy.The authors identified a new compound, 4-tert-butyl-benzaldehyde (4-TBB), which could increase expression and stability of PUM in Drosophila and mice, and had physiochemical properties compatible with clinical use. They pre-treated diverse Drosophila and mouse models of epilepsy with 4-TBB prior to electrical or chemical induction of seizures. The team found that 4-TBB acts as an anticonvulsant, significantly reducing behavioural and physiological signs of seizure. The authors also confirmed that 4-TBB acts – at least in part – through modulation of PUM, as protein levels of downstream targets of PUM were reduced in treated mouse brains and because RNAi-induced reduction of PUM significantly diminished the anticonvulsant activity of 4-TBB in Drosophila.The authors then identified RAB216, a more-potent analogue of 4-TBB, which also increased PUM expression, and induced anticonvulsant activity in Drosophila and mice, at significantly lower concentrations than 4-TBB. Moreover, RAB216 also reduced the duration of seizures in an electrically induced seizure assay within a murine model that recapitulates drug-refractory epilepsy.The Baines lab identified two anticonvulsant compounds that modulate PUM expression and activity to oppose the high neuronal activity associated with seizures. This approach modulates neuronal homeostasis, which may incur fewer side effects, as these mechanisms are tightly controlled to avoid under- or over-activation. Interestingly, although mice were pre-treated with 4-TBB for 3 days prior to seizure induction, there were no overt signs of side effects. However, future work is required to investigate the full mode of action of the new compounds, beyond the modulation of PUM activity. Moreover, as PUM is expressed systemically, the development of compounds targeting central nervous system-specific downstream targets or co-factors of PUM could further minimise potential side effects. Nevertheless, the authors have demonstrated the potential of a novel approach to treating epilepsy, which may reduce the proportion of drug-refractory patients.

585 Cystic fibrosis transmembrane conductance regulator contributes to chloride homeostasis in swine sensory neurons

585 Cystic fibrosis transmembrane conductance regulator contributes to chloride homeostasis in swine sensory neurons

Decreased anterograde transport coupled with sustained retrograde transport contributes to reduced axonal mitochondrial density in tauopathy neurons.

Mitochondria are essential organelle required for neuronal homeostasis. Mitochondria supply ATP and buffer calcium at synaptic terminals. However, the complex structural geometry of neurons poses a unique challenge in transporting mitochondria to synaptic terminals. Kinesin motors supply mitochondria to the axonal compartments, while cytoplasmic dynein is required for retrograde transport. Despite the importance of presynaptic mitochondria, how and whether axonal mitochondrial transport and distribution are altered in tauopathy neurons remain poorly studied. In the current study, we have shown that anterograde transport of mitochondria is reduced in P301L neurons, while there is no change in the retrograde transport. Consistently, axonal mitochondrial abundance is reduced in P301L neurons. We further studied the possible role of two opposing motor proteins on mitochondrial transport and found that mitochondrial association of kinesin is decreased significantly in P301L cells. Interestingly, fitting our experimental data into mathematical equations suggested a possible rise in dynein activity to maintain retrograde flux in P301L cells. Our data indicate that decreased kinesin-mediated transport coupled with sustained retrograde transport might reduce axonal mitochondria in tauopathy neurons, thus contributing to the synaptic deficits in Alzheimer’s disease (AD) and other tauopathies.

MRNA isoform balance in neuronal development and disease.

Balanced mRNA isoform diversity and abundance are spatially and temporally regulated throughout cellular differentiation. The proportion of expressed isoforms contributes to cell type specification and determines key properties of the differentiated cells. Neurons are unique cell types with intricate developmental programs, characteristic cellular morphologies, and electrophysiological potential. Neuron-specific gene expression programs establish these distinctive cellular characteristics and drive diversity among neuronal subtypes. Genes with neuron-specific alternative processing are enriched in key neuronal functions, including synaptic proteins, adhesion molecules, and scaffold proteins. Despite the similarity of neuronal gene expression programs, each neuronal subclass can be distinguished by unique alternative mRNA processing events. Alternative processing of developmentally important transcripts alters coding and regulatory information, including interaction domains, transcript stability, subcellular localization, and targeting by RNA binding proteins. Fine-tuning of mRNA processing is essential for neuronal activity and maintenance. Thus, the focus of neuronal RNA biology research is to dissect the transcriptomic mechanisms that underlie neuronal homeostasis, and consequently, predispose neuronal subtypes to disease. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA in Disease and Development > RNA in Development.

Aging RNA granule dynamics in neurodegeneration.

Disordered RNA-binding proteins and repetitive RNA sequences are the main genetic causes of several neurodegenerative diseases, including amyotrophic lateral sclerosis and Huntington’s disease. Importantly, these components also seed the formation of cytoplasmic liquid-like granules, like stress granules and P bodies. Emerging evidence demonstrates that healthy granules formed via liquid-liquid phase separation can mature into solid- or gel-like inclusions that persist within the cell. These solidified inclusions are a precursor to the aggregates identified in patients, demonstrating that dysregulation of RNA granule biology is an important component of neurodegeneration. Here, we review recent literature highlighting how RNA molecules seed proteinaceous granules, the mechanisms of healthy turnover of RNA granules in cells, which biophysical properties underly a transition to solid- or gel-like material states, and why persistent granules disrupt the cellular homeostasis of neurons. We also identify various methods that will illuminate the contributions of disordered proteins and RNAs to neurodegeneration in ongoing research efforts.

Effects of continuous positive airway pressure treatment on sleep architecture in adults with obstructive sleep apnea and type 2 diabetes.

Obstructive sleep apnea (OSA) severely impacts sleep and has long-term health consequences. Treating sleep apnea with continuous positive airway pressure (CPAP) not only relieves obstructed breathing, but also improves sleep. CPAP improves sleep by reducing apnea-induced awakenings. CPAP may also improve sleep by enhancing features of sleep architecture assessed with electroencephalography (EEG) that maximize sleep depth and neuronal homeostasis, such as the slow oscillation and spindle EEG activity, and by reducing neurophysiological arousal during sleep (i.e., beta EEG activity). We examined cross-sectional differences in quantitative EEG characteristics of sleep, assessed with power spectral analysis, in 29 adults with type 2 diabetes treated with CPAP and 24 adults undergoing SHAM CPAP treatment (total n = 53). We then examined changes in spectral characteristics of sleep as the SHAM group crossed over to active CPAP treatment (n = 19). Polysomnography (PSG) from the CPAP titration night was used for the current analyses. Analyses focused on EEG frequencies associated with sleep maintenance and arousal. These included the slow oscillation (0.5–1 Hz), sigma activity (12–16 Hz, spindle activity), and beta activity (16–20 Hz) in F3, F4, C3, and C4 EEG channels. Whole night non-rapid eye movement (NREM) sleep and the first period of NREM spectral activity were examined. Age and sex were included as covariates. There were no group differences between CPAP and SHAM in spectral characteristics of sleep architecture. However, SHAM cross-over to active CPAP was associated with an increase in relative 12–16 Hz sigma activity across the whole night and a decrease in average beta activity across the whole night. Relative slow oscillation power within the first NREM period decreased with CPAP, particularly for frontal channels. Sigma and beta activity effects did not differ by channel. These findings suggest that CPAP may preferentially enhance spindle activity and mitigate neurophysiological arousal. These findings inform the neurophysiological mechanisms of improved sleep with CPAP and the utility of quantitative EEG measures of sleep as a treatment probe of improvements in neurological and physical health with CPAP.

Familial ALS-associated SFPQ variants promote the formation of SFPQ cytoplasmic aggregates in primary neurons.

Splicing factor proline- and glutamine-rich (SFPQ) is a nuclear RNA-binding protein that is involved in a wide range of physiological processes including neuronal development and homeostasis. However, the mislocalization and cytoplasmic aggregation of SFPQ are associated with the pathophysiology of amyotrophic lateral sclerosis (ALS). We have previously reported that zinc mediates SFPQ polymerization and promotes the formation of cytoplasmic aggregates in neurons. Here we characterize two familial ALS (fALS)-associated SFPQ variants, which cause amino acid substitutions in the proximity of the SFPQ zinc-coordinating centre (N533H and L534I). Both mutants display increased zinc-binding affinities, which can be explained by the presence of a second zinc-binding site revealed by the 1.83 Å crystal structure of the human SFPQ L534I mutant. Overexpression of these fALS-associated mutants significantly increases the number of SFPQ cytoplasmic aggregates in primary neurons. Although they do not affect the density of dendritic spines, the presence of SFPQ cytoplasmic aggregates causes a marked reduction in the levels of the GluA1, but not the GluA2 subunit of AMPA-type glutamate receptors on the neuronal surface. Taken together, our data demonstrate that fALS-associated mutations enhance the propensity of SFPQ to bind zinc and form aggregates, leading to the dysregulation of AMPA receptor subunit composition, which may contribute to neuronal dysfunction in ALS.

Extracellular transglutaminase-2, nude or associated with astrocytic extracellular vesicles, modulates neuronal calcium homeostasis.

We have uncovered a novel role for astrocytes-derived extracellular vesicles (EVs) in controlling intraneuronal Ca2+ concentration ([Ca2+]i) and identified transglutaminase-2 (TG2) as a surface-cargo of astrocytes-derived EVs. Incubation of hippocampal neurons with primed astrocyte-derived EVs have led to an increase in [Ca2+]i, unlike EVs from TG2-knockout astrocytes. Exposure of neurons or brain slices to extracellular TG2 promoted a [Ca2+]i rise, which was reversible upon TG2 removal and was dependent on Ca2+ influx through the plasma membrane. Patch-clamp and calcium imaging recordings revealed TG2-dependent neuronal membrane depolarization and activation of inward currents, due to the Na+/Ca2+-exchanger (NCX) operating in the reverse mode and indirect activation of L-type VOCCs, as indicated by VOCCs/NCX pharmacological inhibitors. A subunit of Na+/K+-ATPase was selected by comparative proteomics and identified as being functionally inhibited by extracellular TG2, implicating Na+/K+-ATPase inhibition in NCX reverse mode-switching leading to Ca2+ influx and higher basal [Ca2+]i. These data suggest that reactive astrocytes control intraneuronal [Ca2+]i through release of EVs with TG2 as responsible cargo, which could have a significant impact on synaptic activity in brain inflammation.

The Potential of Small Molecules to Modulate the Mitochondria-Endoplasmic Reticulum Interplay in Alzheimer's Disease.

Alzheimer’s disease (AD) is the most common neurodegenerative disease affecting a growing number of elderly individuals. No disease-modifying drugs have yet been identified despite over 30 years of research on the topic, showing the need for further research on this multifactorial disease. In addition to the accumulation of amyloid β-peptide (Aβ) and hyperphosphorylated tau (p-tau), several other alterations have been associated with AD such as calcium (Ca2+) signaling, glucose-, fatty acid-, cholesterol-, and phospholipid metabolism, inflammation, and mitochondrial dysfunction. Interestingly, all these processes have been associated with the mitochondria–endoplasmic reticulum (ER) contact site (MERCS) signaling hub. We and others have hypothesized that the dysregulated MERCS function may be one of the main pathogenic pathways driving AD pathology. Due to the variety of biological processes overseen at the MERCS, we believe that they constitute unique therapeutic targets to boost the neuronal function and recover neuronal homeostasis. Thus, developing molecules with the capacity to correct and/or modulate the MERCS interplay can unleash unique therapeutic opportunities for AD. The potential pharmacological intervention using MERCS modulators in different models of AD is currently under investigation. Here, we survey small molecules with the potential to modulate MERCS structures and functions and restore neuronal homeostasis in AD. We will focus on recently reported examples and provide an overview of the current challenges and future perspectives to develop MERCS modulators in the context of translational research.

Pomegranate (Punica granatum L.) Attenuates Neuroinflammation Involved in Neurodegenerative Diseases.

Food scientists have studied the many health benefits of polyphenols against pernicious human diseases. Evidence from scientific studies has shown that earlier healthy lifestyle changes, particularly in nutrition patterns, can reduce the burden of age-related diseases. In this context, a large number of plant-derived components belonging to the class of polyphenols have been reported to possess neuroprotective benefits. In this review, we examined studies on the effect of dietary polyphenols, notably from Punica granatum L., on neurodegenerative disease, including Alzheimer’s disease, which is symptomatically characterized by impairment of cognitive functions. Clinical trials are in favor of the role of some polyphenols in maintaining neuronal homeostasis and attenuating clinical presentations of the disease. However, discrepancies in study design often bring inconsistent findings on the same component and display differences in their effectiveness due to interindividual variability, bioavailability in the body after administration, molecular structures, cross-blood-brain barrier, and signaling pathways such as nuclear factor kappa B (NF-κB). Based on preclinical and clinical trials, it appears that pomegranate may prove valuable in treating neurodegenerative disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). Therefore, due to the lack of information on human clinical trials, future in-depth studies, focusing on human beings, of several bioactive components of pomegranate’s polyphenols and their synergic effects should be carried out to evaluate their curative treatment.

Deregulation of Mitochondrial Calcium Handling Due to Presenilin Loss Disrupts Redox Homeostasis and Promotes Neuronal Dysfunction.

Mitochondrial dysfunction and oxidative stress are major contributors to the pathophysiology of neurodegenerative diseases, including Alzheimer’s disease (AD). However, the mechanisms driving mitochondrial dysfunction and oxidative stress are unclear. Familial AD (fAD) is an early onset form of AD caused primarily by mutations in the presenilin-encoding genes. Previously, using Caenorhabditis elegans as a model system to study presenilin function, we found that loss of C. elegans presenilin orthologue SEL-12 results in elevated mitochondrial and cytosolic calcium levels. Here, we provide evidence that elevated neuronal mitochondrial generated reactive oxygen species (ROS) and subsequent neurodegeneration in sel-12 mutants are a consequence of the increase of mitochondrial calcium levels and not cytosolic calcium levels. We also identify mTORC1 signaling as a critical factor in sustaining high ROS in sel-12 mutants in part through its repression of the ROS scavenging system SKN-1/Nrf. Our study reveals that SEL-12/presenilin loss disrupts neuronal ROS homeostasis by increasing mitochondrial ROS generation and elevating mTORC1 signaling, which exacerbates this imbalance by suppressing SKN-1/Nrf antioxidant activity.

Genomic targets and selective inhibition of DNA methyltransferase isoforms

BackgroundDNA methylation in the human genome is established and maintained by DNA methyltransferases (DNMTs). DNMT isoforms show differential expression by cell lineage and during development, but much remains to be elucidated about their shared and unique genomic targets.ResultsWe examined changes in the epigenome following overexpression of 13 DNMT isoforms in HEK293T cells. We observed increased methylation (Δβ > 0.2) at 43,405 CpG sites, with expression of DNMT3A2, DNMTΔ3B4 and DNMTΔ3B2 associated with the greatest impact. De novo methylation occurred primarily within open sea regions and at loci with intermediate methylation levels (β: 0.2–0.6). 53% of differentially methylated loci showed specificity towards a single DNMT subfamily, primarily DNMTΔ3B and DNMT3A and 39% towards a single isoform. These loci were significantly enriched for pathways related to neuronal development (DNMTΔ3B4), calcium homeostasis (DNMTΔ3B3) and ion transport (DNMT3L). Repetitive elements did not display differential sensitivity to overexpressed DNMTs, but hypermethylation of Alu elements was associated with their evolutionary age following overexpression of DNMT3A2, DNMT3B1, DNMT3B2 and DNMT3L. Differential methylation (Δβ > 0.1) was observed at 121 of the 353 loci associated with the Horvath ‘epigenetic clock’ model of ageing, with 51 showing isoform specificity, and was associated with reduction of epigenetic age by 5–15 years following overexpression of seven isoforms. Finally, we demonstrate the potential for dietary constituents to modify epigenetic marks through isoform-specific inhibition of methylation activity.ConclusionsOur results provide insight into regions of the genome methylated uniquely by specific DNMT isoforms and demonstrate the potential for dietary intervention to modify the epigenome.

Controlled Tau Cleavage in Cells Reveals Abnormal Localizations of Tau Fragments

In several forms of dementia, such as Alzheimer’s disease, the cytoskeleton-associated protein tau undergoes proteolysis, giving rise to fragments that have a toxic impact on neuronal homeostasis. How these fragments interact with cellular structures, in particular with the cytoskeleton, is currently incompletely understood. Here, we developed a method, derived from a Tobacco Etch Virus (TEV) protease system, to induce controlled cleavage of tau at specific sites. Five tau proteins containing specific TEV recognition sites corresponding to pathological proteolytic sites were engineered, and tagged with GFP at one end and mCherry at the other. After a controlled cleavage to produce GFP-N-terminal and C-terminal-mCherry fragments, we followed the fate of tau fragments in cells. Our results showed that whole engineered tau proteins associate with the cytoskeleton similarly to the non-modified tau, whereas tau fragments adopted different localizations with respect to the actin and microtubule cytoskeletons. These distinct localizations were confirmed by expressing each separate fragment in cells. Some cleavages – in particular cleavages at amino-acid positions 124 or 256 – displayed a certain level of cellular toxicity, with an unusual relocalization of the N-terminal fragments to the nucleus. Based on the data presented here, inducible cleavage of tau by the TEV protease appears to be a valuable tool to reproduce tau fragmentation in cells and study the resulting consequences on cell physiology.

High-frequency stimulation of the subthalamic nucleus induces a sustained inhibition of serotonergic system via loss of cell phenotype

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become a standard treatment for Parkinson’s disease (PD). However, in a considerable number of patients debilitating psychiatric side-effects occur. Recent research has revealed that external stimuli can alter the neurotransmitters’ homeostasis in neurons, which is known as “neurotransmitter respecification”. Herein, we addressed if neurotransmitter respecification could be a mechanism by which DBS suppresses the serotonergic function in the dorsal raphe nucleus (DRN) leading to mood changes. We infused transgenic 5-HT-Cre (ePET-Cre) mice with AAV viruses to achieve targeted expression of eYFP and the genetically encoded calcium indicator GCaMP6s in the DRN prior to methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. Mice received bilateral DBS electrodes in the STN and an optic fiber in the DRN for calcium photometry. MPTP-treated mice demonstrated behavioral and histological PD phenotype, whereas all STN-DBS animals exhibited an increased immobility time in the forced swim test, reduced calcium activity, and loss of tryptophan hydroxylase-2 expression in the DRN. Given the prominent role of calcium transients in mediating neurotransmitter respecification, these results suggest a loss of serotonergic phenotype in the DRN following STN-DBS. These findings indicate that loss of serotonergic cell phenotype may underlie the unwanted depressive symptoms following STN-DBS.

Diverse Roles of Ceramide in the Progression and Pathogenesis of Alzheimer's Disease.

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, and is associated with several pathophysiological features, including cellular dysfunction, failure of neurotransmission, cognitive impairment, cell death, and other clinical consequences. Advanced research on the pathogenesis of AD has elucidated a mechanistic framework and revealed many therapeutic possibilities. Among the mechanisms, sphingolipids are mentioned as distinctive mediators to be associated with the pathology of AD. Reportedly, alteration in the metabolism of sphingolipids and their metabolites result in the dysfunction of mitochondria, autophagy, amyloid beta regulation, and neuronal homeostasis, which exacerbates AD progression. Considering the importance of sphingolipids, in this review, we discuss the role of ceramide, a bioactive sphingolipid metabolite, in the progression and pathogenesis of AD. Herein, we describe the ceramide synthesis pathway and its involvement in the dysregulation of homeostasis, which eventually leads to AD. Furthermore, this review references different therapeutics proposed to modulate the ceramide pathway to maintain ceramide levels and prevent the disease progression.

Local mRNA translation and cytoskeletal reorganization: Mechanisms that tune neuronal responses.

Neurons are highly polarized cells with significantly long axonal and dendritic extensions that can reach distances up to hundreds of centimeters away from the cell bodies in higher vertebrates. Their successful formation, maintenance, and proper function highly depend on the coordination of intricate molecular networks that allow axons and dendrites to quickly process information, and respond to a continuous and diverse cascade of environmental stimuli, often without enough time for communication with the soma. Two seemingly unrelated processes, essential for these rapid responses, and thus neuronal homeostasis and plasticity, are local mRNA translation and cytoskeletal reorganization. The axonal cytoskeleton is characterized by high stability and great plasticity; two contradictory attributes that emerge from the powerful cytoskeletal rearrangement dynamics. Cytoskeletal reorganization is crucial during nervous system development and in adulthood, ensuring the establishment of proper neuronal shape and polarity, as well as regulating intracellular transport and synaptic functions. Local mRNA translation is another mechanism with a well-established role in the developing and adult nervous system. It is pivotal for axonal guidance and arborization, synaptic formation, and function and seems to be a key player in processes activated after neuronal damage. Perturbations in the regulatory pathways of local translation and cytoskeletal reorganization contribute to various pathologies with diverse clinical manifestations, ranging from intellectual disabilities (ID) to autism spectrum disorders (ASD) and schizophrenia (SCZ). Despite the fact that both processes are essential for the orchestration of pathways critical for proper axonal and dendritic function, the interplay between them remains elusive. Here we review our current knowledge on the molecular mechanisms and specific interaction networks that regulate and potentially coordinate these interconnected processes.

Sex Differentially Alters Secretion of Brain Extracellular Vesicles During Aging: A Potential Mechanism for Maintaining Brain Homeostasis

Extracellular vesicles (EVs) in the brain play a role in neuronal homeostasis by removing intracellular material and regulating cell-to-cell communication. Given that sex and aging differentially modulate brain networks, we investigated sex-dependent differences in EV levels and content in the brain during aging. EVs were isolated from the brains of 3, 6, 12, 18, and 24 month-old female and male C57BL/6 J mice, and the levels of different EV species determined. While the number of plasma membrane-derived microvesicles and a subset of late endosomes-derived exosomes increased with age in the brain of female mice, no significant changes were seen in males. Mitochondria-derived mitovesicles in the brain increased during aging in both sexes, a change that may reflect aging-dependent alterations in mitochondrial function. These findings reveal enhanced turnover during aging in female brains, suggesting a mechanism for advantageous successful female brain aging and sex-depending different susceptibility to age-related neurodegenerative diseases.