TMEM16F regulates pathologic α-synuclein secretion and spread in cellular and mouse models of Parkinson's disease.

One of the main hallmarks of Parkinson's disease (PD) pathology is the spread of the aggregate-prone protein α-synuclein (α-syn), which can be detected in the plasma and cerebrospinal fluid of patients as well as in the extracellular environment of neuronal cells. The secreted α-syn can exhibit "prion-like" behavior and transmission to naïve cells can promote conformational changes and pathology. The precise role of plasma membrane proteins in the pathologic process of α-syn is yet to be fully resolved.

Device for detection of activity-dependent changes in neural spheroids at MHz and GHz frequencies.

Intracellular processes triggered by neural activity include changes in ionic concentrations, protein release, and synaptic vesicle cycling. These processes play significant roles in neurological disorders. The beneficial effects of brain stimulation may also be mediated through intracellular changes.

Sympathetic response following unannounced loss of balance during walking in young adults: laboratory study.

An unannounced balance loss during walking, i.e., balance perturbation, is a stressful event, which changes the activity of the sympathetic nervous system (SNS).

Characteristics of Unsuccessful Balance Reactive Responses to Lateral Loss of Balance in Older Adults.

Introduction: An effective reactive step response to an unexpected balance loss is an important factor that determines if a fall will happen. We investigated reactive step strategies and kinematics of unsuccessful balance recovery responses that ended with falls in older adults.

Methods: We compared the strategies and kinematics of reactive stepping after a lateral loss of balance, i.

Disease-associated polyalanine expansion mutations impair UBA6-dependent ubiquitination.

Expansion mutations in polyalanine stretches are associated with a growing number of diseases sharing a high degree of genotypic and phenotypic commonality. These similarities prompted us to query the normal function of physiological polyalanine stretches and to investigate whether a common molecular mechanism is involved in these diseases. Here, we show that UBA6, an E1 ubiquitin-activating enzyme, recognizes a polyalanine stretch within its cognate E2 ubiquitin-conjugating enzyme USE1.

Brain-Targeted Liposomes Loaded with Monoclonal Antibodies Reduce Alpha-Synuclein Aggregation and Improve Behavioral Symptoms in Parkinson's Disease.

Monoclonal antibodies (mAbs) hold promise in treating Parkinson's disease (PD), although poor delivery to the brain hinders their therapeutic application. In the current study, it is demonstrated that brain-targeted liposomes (BTL) enhance the delivery of mAbs across the blood-brain-barrier (BBB) and into neurons, thereby allowing the intracellular and extracellular treatment of the PD brain. BTL are decorated with transferrin to improve brain targeting through overexpressed transferrin-receptors on the BBB during PD.

Oculopharyngeal muscular dystrophy mutations link the RNA-binding protein HNRNPQ to autophagosome biogenesis.

Autophagy is an intracellular degradative process with an important role in cellular homeostasis. Here, we show that the RNA binding protein (RBP), heterogeneous nuclear ribonucleoprotein Q (HNRNPQ)/SYNCRIP is required to stimulate early events in autophagosome biogenesis, in particular the induction of VPS34 kinase by ULK1-mediated beclin 1 phosphorylation. The RBPs HNRNPQ and poly(A) binding protein nuclear 1 (PABPN1) form a regulatory network that controls the turnover of distinct autophagy-related (ATG) proteins.

3D models of glioblastoma interaction with cortical cells.

Glioblastoma (GBM) invasiveness and ability to infiltrate deep into the brain tissue is a major reason for the poor patient prognosis for this type of brain cancer. Behavior of glioblastoma cells, including their motility, and expression of invasion-promoting genes such as matrix metalloprotease-2 (MMP2), are strongly influenced by normal cells found in the brain parenchyma. Cells such as neurons may also be influenced by the tumor, as many glioblastoma patients develop epilepsy.

Efficient and Accurate Computational Model of Neuron with Spike Frequency Adaptation.

Simplified models of neurons are widely used in computational investigations of large networks. One of the most important performance metrics of simplified models is their accuracy in reproducing action potential (spike) timing. In this article, we developed a simple, computationally efficient neuron model by modifying the adaptive exponential integrate and fire (AdEx) model [1] with sigmoid afterhyperpolarization current (Sigmoid AHP).

Understanding the Impact of Neural Variations and Random Connections on Inference.

Recent research suggests that neural networks created from dissociated neurons may be used for computing and performing machine learning tasks. To develop a better artificial intelligent system, a hybrid bio-silicon computer is worth exploring, but its performance is still inferior to that of a silicon-based computer. One reason may be that a living neural network has many intrinsic properties, such as random network connectivity, high network sparsity, and large neural and synaptic variability.

Neuron and astrocyte aggregation and sorting in three-dimensional neuronal constructs.

Aggregation and self-sorting of cells in three dimensional cultures have been described for non-neuronal cells. Despite increased interest in engineered neural tissues for treating brain injury or for modeling neurological disorders in vitro, little data is available on collective cell movements in neuronal aggregates. Migration and sorting of cells may alter these constructs' morphology and, therefore, the function of their neural circuitry.

The molecular basis of Rac-GTP action-promoting binding of p67 to Nox2 by disengaging the β hairpin from downstream residues.

p67 fulfils a key role in the assembly/activation of the NADPH oxidase by direct interaction with Nox2. We proposed that Rac-GTP serves both as a carrier of p67 to the membrane and an inducer of a conformational change enhancing its affinity for Nox2. This study provides evidence for the latter function: (i) oxidase activation was inhibited by p67 peptides (106-120) and (181-195), corresponding to the β hairpin and to a downstream region engaged in intramolecular bonds with the β hairpin, respectively; (ii) deletion of residues 181-193 and point mutations Q115R or K181E resulted in selective binding of p67 to Nox2 peptide (369-383); (iii) both deletion and point mutations led to a change in p67 , expressed in increased apparent molecular weights; (iv) p67 was bound to p67 peptide (181-195) and to a cluster of peptides (residues 97-117), supporting the participation of selected residues within these sequences in intramolecular bonds; (v) p67 failed to bind to Nox2 peptide (369-383), following interaction with Rac1-GTP, but a (p67 -Rac1-GTP) chimera exhibited marked binding to the peptide, similar to that of p67 deletion and point mutants; and (vi) size exclusion chromatography of the chimera revealed its partition in monomeric and polymeric forms, with binding to Nox2 peptide (369-383) restricted to polymers.

Deubiquitylating enzymes in neuronal health and disease.

Ubiquitylation and deubiquitylation play a pivotal role in protein homeostasis (proteostasis). Proteostasis shapes the proteome landscape in the human brain and its impairment is linked to neurodevelopmental and neurodegenerative disorders. Here we discuss the emerging roles of deubiquitylating enzymes in neuronal function and survival.

Variability of seizure-like activity in an model of epilepsy depends on the electrical recording method.

Background: Hippocampal and cortical slice-based models are widely used to study seizures and epilepsy. Seizure detection and quantification are essential components for studying mechanisms of epilepsy and assessing therapeutic interventions. To obtain meaningful signals and maximize experimental throughput, variability should be minimized.

Micro Three-Dimensional Neuronal Cultures Generate Developing Cortex-Like Activity Patterns.

Studies aimed at neurological drug discovery have been carried out both and . cell culture models have showed potential as drug testing platforms characterized by high throughput, low cost, good reproducibility and ease of handling and observation. However, neuronal culture models are facing challenges in replicating -like activity patterns.

p67 -derived self-assembled peptides prevent Nox2 NADPH oxidase activation by an auto-inhibitory mechanism.

Activation of the Nox2-dependent NADPH oxidase is the result of a conformational change in Nox2 induced by interaction with the cytosolic component p67 . In preliminary work we identified a cluster of overlapping 15-mer synthetic peptides, corresponding to p67 residues 259-279, which inhibited oxidase activity in an in vitro, cell-free assay, but the results did not point to a competitive mechanism. We recently identified an auto-inhibitory intramolecular bond in p67 , one extremity of which was located within the 259-279 sequence, and we hypothesized that inhibition by exogenous peptides might mimic intrinsic auto-inhibition.

p67 binds to a newly identified site in Nox2 following the disengagement of an intramolecular bond-Canaan sighted?

Activation of the phagocyte NADPH oxidase involves a conformational change in Nox2. The effector in this process is p67 and there is evidence for a change in the configuration of p67 being required for binding to Nox2. To study this, we measured binding of p67 to a library of Nox2 peptides and binding of NusA-Nox2 fusion proteins to p67 .

Neural layer self-assembly in geometrically confined rat and human 3D cultures.

Neurological disorders affect millions of Americans and this number is expected to rise with the aging population. Development of drugs to treat these disorders may be facilitated by improved in vitro models that faithfully reproduce salient features of the relevant brain regions. Current 3D culture methods face challenges with reliably reproducing microarchitectural features of brain morphology such as cortical or hippocampal layers.

Kinase Inhibitors with Antiepileptic Properties Identified with a Novel in Vitro Screening Platform.

Kinase signaling plays an important role in acquired epilepsy, but only a small percentage of the total kinome has been investigated in this context. A major roadblock that prevents the systematic investigation of the contributions of kinase signaling networks is the slow speed of experiments designed to test the chronic effects of target inhibition in epilepsy models. We developed a novel in vitro screening platform based on microwire recordings from an organotypic hippocampal culture model of acquired epilepsy.

Epilepsy-on-a-Chip System for Antiepileptic Drug Discovery.

Objective: Hippocampal slice cultures spontaneously develop chronic epilepsy several days after slicing and are used as an in vitro model of post-traumatic epilepsy. Here, we describe a hybrid microfluidic-microelectrode array (μflow-MEA) technology that incorporates a microfluidic perfusion network and electrodes into a miniaturized device for hippocampal slice culture based antiepileptic drug discovery.

Methods: Field potential simulation was conducted to help optimize the electrode design to detect a seizure-like population activity.

Binding of p67 to Nox2 is stabilized by disulfide bonds between cysteines in the Cys-Gly-Cys triad in Nox2 and in p67.

A central event in the activation of the phagocyte NADPH oxidase involves binding of p67 to the dehydrogenase region of Nox2. The identity of the binding site in Nox2 is unknown. By measuring binding of p67 to synthetic Nox2 peptides, we previously identified a sequence corresponding to Nox2 residues 357-383, as a potential binding site.