Virus-mediated delivery of single-chain antibody targeting TDP-43 protects against neuropathology, cognitive impairment and motor deficit caused by chronic cerebral hypoperfusion.

Chronic cerebral hypoperfusion induced by permanent unilateral common carotid artery occlusion in mice was recently found to induce an age-dependent formation of insoluble cytoplasmic TDP-43 aggregates reminiscent of pathological changes found in human vascular dementia. In this model, the gradual deregulation of TDP-43 homeostasis in cortical neurons was associated with marked cognitive and motor deficits. To target the TDP-43-mediated toxicity in this model, we generated an adeno-associated virus vector encoding a single-chain antibody against TDP-43, called scFv-E6, designed for pan-neuronal transduction following intravenous administration.

Inhibition of NF-κB with an Analog of Withaferin-A Restores TDP-43 Homeostasis and Proteome Profiles in a Model of Sporadic ALS.

The current knowledge on pathogenic mechanisms in amyotrophic lateral sclerosis (ALS) has widely been derived from studies with cell and animal models bearing ALS-linked genetic mutations. However, it remains unclear to what extent these disease models are of relevance to sporadic ALS. Few years ago, we reported that the cerebrospinal fluid (CSF) from sporadic ALS patients contains toxic factors for disease transmission in mice via chronic intracerebroventricular (i.

Tryptophan residues in TDP-43 and SOD1 modulate the cross-seeding and toxicity of SOD1.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of motor neurons. Neuronal superoxide dismutase-1 (SOD1) inclusion bodies are characteristic of familial ALS with SOD1 mutations, while a hallmark of sporadic ALS is inclusions containing aggregated WT TAR DNA-binding protein 43 (TDP-43). We show here that co-expression of mutant or WT TDP-43 with SOD1 leads to misfolding of endogenous SOD1 and aggregation of SOD1 reporter protein SOD1-GFP in human cell cultures and promotes synergistic axonopathy in zebrafish.

Neuronal dysfunction caused by FUSR521G promotes ALS-associated phenotypes that are attenuated by NF-κB inhibition.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are related neurodegenerative diseases that belong to a common disease spectrum based on overlapping clinical, pathological and genetic evidence. Early pathological changes to the morphology and synapses of affected neuron populations in ALS/FTD suggest a common underlying mechanism of disease that requires further investigation. Fused in sarcoma (FUS) is a DNA/RNA-binding protein with known genetic and pathological links to ALS/FTD.

Ultrasensitive digital immunoassays for SOD1 conformation in amyotrophic lateral sclerosis.

The aim of this study was to detect misfolded Cu/Zn SOD1 as a potential biomarker for amyotrophic lateral sclerosis (ALS). Two ultrasensitive immunodetection assays were developed for the quantification of total and misfolded SOD1. The detection of total and misfolded SOD1 was possible in human serum and cerebrospinal fluid.

Emerging Trends in the Field of Inflammation and Proteinopathy in ALS/FTD Spectrum Disorder.

Proteinopathy and neuroinflammation are two main hallmarks of neurodegenerative diseases. They also represent rare common events in an exceptionally broad landscape of genetic, environmental, neuropathologic, and clinical heterogeneity present in patients. Here, we aim to recount the emerging trends in amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) spectrum disorder.

Axonal Transport Defect in Gigaxonin Deficiency Rescued by Tubastatin A.

Giant axonal neuropathy (GAN) is a disease caused by a deficiency of gigaxonin, a mediator of the degradation of intermediate filament (IF) proteins. A lack of gigaxonin alters the turnover of IF proteins, provoking accumulation and disorganization of neurofilaments (NFs) in neurons, a hallmark of the disease. However, the effects of IF disorganization on neuronal function remain unknown.

A New Mouse Model of Giant Axonal Neuropathy with Overt Phenotypes and Neurodegeneration Driven by Neurofilament Disorganization.

Research on pathogenic mechanisms underlying giant axonal neuropathy (GAN), a disease caused by a deficiency of gigaxonin, has been hindered by the lack of appropriate animal models exhibiting substantial symptoms and large neurofilament (NF) swellings, a hallmark of the human disease. It is well established that intermediate filament (IF) proteins are substrates for gigaxonin-mediated degradation. However, it has remained unknown to what extent NF accumulations contribute to GAN pathogenesis.

Distinct Plasma Immune Profile in ALS Implicates sTNFR-II in pAMPK/Leptin Homeostasis.

Amyotrophic lateral sclerosis (ALS) is a clinically highly heterogeneous disease with a survival rate ranging from months to decades. Evidence suggests that a systemic deregulation of immune response may play a role and affect disease progression. Here, we measured 62 different immune/metabolic mediators in plasma of sporadic ALS (sALS) patients.

Noise-induced hearing loss vulnerability in type III intermediate filament peripherin gene knockout mice.

In the post-natal mouse cochlea, type II spiral ganglion neurons (SGNs) innervating the electromotile outer hair cells (OHCs) of the 'cochlear amplifier' selectively express the type III intermediate filament peripherin gene (. Immunolabeling showed that knockout (KO) mice exhibited disruption of this (outer spiral bundle) afferent innervation, while the radial fiber (type I SGN) innervation of the inner hair cells (~95% of the SGN population) was retained. Functionality of the medial olivocochlear (MOC) efferent innervation of the OHCs was confirmed in the KO, based on suppression of distortion product otoacoustic emissions (DPOAEs) direct electrical stimulation.

Neurofilament Transport Is Bidirectional .

Neurofilaments are abundant space-filling cytoskeletal polymers that are transported into and along axons. During postnatal development, these polymers accumulate in myelinated axons causing an expansion of axon caliber, which is necessary for rapid electrical transmission. Studies on cultured nerve cells have shown that axonal neurofilaments move rapidly and intermittently along microtubule tracks in both anterograde and retrograde directions.

Targeting TDP-43 Pathology Alleviates Cognitive and Motor Deficits Caused by Chronic Cerebral Hypoperfusion.

Vascular dementia is one of the most common forms of dementia in aging population. However, the molecular mechanisms involved in development of disease and the link between the cerebrovascular pathology and the cognitive impairments remain elusive. Currently, one common and/or converging neuropathological pathway leading to dementia is the mislocalization and altered functionality of the TDP-43.

Induction of autophagy mitigates TDP-43 pathology and translational repression of neurofilament mRNAs in mouse models of ALS/FTD.

Background: TDP-43 proteinopathy is a pathological hallmark of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). So far, there is no therapy available for these neurodegenerative diseases. In addition, the impact of TDP-43 proteinopathy on neuronal translational profile also remains unknown.

Withaferin-A Treatment Alleviates TAR DNA-Binding Protein-43 Pathology and Improves Cognitive Function in a Mouse Model of FTLD.

Withaferin-A, an active withanolide derived from the medicinal herbal plant Withania somnifera induces autophagy, reduces TDP-43 proteinopathy, and improves cognitive function in transgenic mice expressing mutant TDP-43 modelling FTLD. TDP-43 is a nuclear DNA/RNA-binding protein with cellular functions in RNA transcription and splicing. Abnormal cytoplasmic aggregates of TDP-43 occur in several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and limbic-predominant age-related TDP-43 encephalopathy (LATE).

Monoclonal full-length antibody against TAR DNA binding protein 43 reduces related proteinopathy in neurons.

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), 2 incurable neurodegenerative disorders, share the same pathological hallmark named TDP43 (TAR DNA binding protein 43) proteinopathy. This event is characterized by a consistent cytoplasmic mislocalization and aggregation of the protein TDP43, which loses its physiological properties, leading neurons to death. Antibody-based approaches are now emerging interventions in the field of neurodegenerative disorders.

Modeling of Electronic Mobilities in Halide Perovskites: Adiabatic Quantum Localization Scenario.

The transport properties of MAPbI3 are analyzed within a tight-binding model. We find a strong Fröhlich interaction of electron and holes with the electrostatic potential induced by the longitudinal optical phonon modes. This potential induces a strong scattering and limits the electronic mobilities at room temperature to about 200  cm^{2}/V s.

Mitigation of ALS Pathology by Neuron-Specific Inhibition of Nuclear Factor Kappa B Signaling.

To investigate the role of neuronal NF-κB activity in pathogenesis of amyotrophic lateral sclerosis (ALS), we generated transgenic mice with neuron-specific expression of a super-repressor form of the NF-κB inhibitor (IκBα-SR), which were then crossed with mice of both sexes, expressing ALS-linked gene mutants for TAR DNA-binding protein (TDP-43) and superoxide dismutase 1 (SOD1). Remarkably, neuronal expression of IκBα-SR transgene in mice expressing TDP-43 or TDP-43 mice led to a decrease in cytoplasmic to nuclear ratio of human TDP-43. The mitigation of TDP-43 neuropathology by IκBα-SR, which is likely due to an induction of autophagy, was associated with amelioration of cognitive and motor deficits as well as reduction of motor neuron loss and gliosis.

Neurofilaments: neurobiological foundations for biomarker applications.

Interest in neurofilaments has risen sharply in recent years with recognition of their potential as biomarkers of brain injury or neurodegeneration in CSF and blood. This is in the context of a growing appreciation for the complexity of the neurobiology of neurofilaments, new recognition of specialized roles for neurofilaments in synapses and a developing understanding of mechanisms responsible for their turnover. Here we will review the neurobiology of neurofilament proteins, describing current understanding of their structure and function, including recently discovered evidence for their roles in synapses.

Transmission of ALS pathogenesis by the cerebrospinal fluid.

To test the hypothesis that the cerebrospinal fluid (CSF) could provide a spreading route for pathogenesis of amyotrophic lateral sclerosis (ALS), we have examined the effects of intraventricular infusion during 2 weeks of pooled CSF samples from sporadic ALS patients or control CSF samples into transgenic mice expressing human TDP43 which do not develop pathological phenotypes. Infusion of ALS-CSF, but not of control CSF, triggered motor and cognitive dysfunction, as well as ALS-like pathological changes including TDP43 proteinopathy, neurofilament disorganization and neuroinflammation. In addition, the neuron-specific translational profiles from peptide analyses of immunoprecipitated ribosomes revealed dysregulation of multiple protein networks in response to ALS-CSF altering cytoskeletal organization, vesicle trafficking, mitochondrial function, and cell metabolism.

Key role of UBQLN2 in pathogenesis of amyotrophic lateral sclerosis and frontotemporal dementia.

Ubiquilin-2 (UBQLN2) is a member of the ubiquilin family, actively implicated in the degradation of misfolded and redundant proteins through the ubiquitin-proteasome system and macroautophagy. UBQLN2 received much attention after the discovery of gene mutations in amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). The abnormal presence of positive UBQLN2 inclusion in the cytosol of degenerating motor neurons of familial and sporadic forms of ALS patients has been newly related to neurodegeneration.

Virus-mediated delivery of antibody targeting TAR DNA-binding protein-43 mitigates associated neuropathology.

The cytoplasmic aggregation of TAR DNA-binding protein-43 (TDP-43) is a hallmark of degenerating neurons in amyotrophic lateral sclerosis (ALS) and subsets of frontotemporal dementia (FTD). In order to reduce TDP-43 pathology, we generated single-chain (scFv) antibodies against the RNA recognition motif 1 (RRM1) of TDP-43, which is involved in abnormal protein self-aggregation and interaction with p65 NF-κB. Virus-mediated delivery into the nervous system of a scFv antibody, named VH7Vk9, reduced microgliosis in a mouse model of acute neuroinflammation and mitigated cognitive impairment, motor defects, TDP-43 proteinopathy, and neuroinflammation in transgenic mice expressing ALS-linked TDP-43 mutations.

Local Acceleration of Neurofilament Transport at Nodes of Ranvier.

Myelinated axons are constricted at nodes of Ranvier. These constrictions are important physiologically because they increase the speed of saltatory nerve conduction, but they also represent potential bottlenecks for the movement of axonally transported cargoes. One type of cargo are neurofilaments, which are abundant space-filling cytoskeletal polymers that function to increase axon caliber.