In Vivo Nanodiamond Quantum Sensing of Free Radicals in Caenorhabditis elegans Models.

Free radicals are believed to play a secondary role in the cell death cascade associated with various diseases. In Huntington's disease (HD), the aggregation of polyglutamine (PolyQ) not only contributes to the disease but also elevates free radical levels. However, measuring free radicals is difficult due to their short lifespan and limited diffusion range.

Rebalancing the motor circuit restores movement in a Caenorhabditis elegans model for TDP-43 toxicity.

Amyotrophic lateral sclerosis can be caused by abnormal accumulation of TAR DNA-binding protein 43 (TDP-43) in the cytoplasm of neurons. Here, we use a C. elegans model for TDP-43-induced toxicity to identify the biological mechanisms that lead to disease-related phenotypes.

Neuronal overexpression of hTDP-43 in impairs motor function.

Transactive response DNA binding-protein 43 (TDP-43) is a conserved RNA/DNA-binding protein with a role in RNA metabolism and homeostasis. Aberrant TDP-43 functioning has been considered a major culprit in amyotrophic lateral sclerosis (ALS). can be used to phenocopy ALS .

Neuronal overexpression of hTDP-43 in mimics the cellular pathology commonly observed in TDP-43 proteinopathies.

Inclusions consisting of transactive response DNA-binding protein 43 (TDP-43) are a characteristic feature of amyotrophic lateral sclerosis (ALS). has been instrumental in studying the underlying mechanisms of TDP-43 pathology. Here, we extend the possibilities of previous studies by examining a model expressing human wild-type ( ) pan-neuronally.

Neuronal overexpression of hTDP-43 in impairs different neuronally controlled behaviors and decreases fecundity.

Cytoplasmic inclusions consisting of transactive response DNA-binding protein 43 (TDP-43) are a key hallmark of TDP-43 proteinopathies like amyotrophic lateral sclerosis (ALS). is considered a useful model for studying the molecular mechanisms underlying TDP-43 toxicity . Here, we assessed different neuronal systems through established behavioral assays and extended the phenotypic characterisation of a model expressing wildtype human ( ) pan-neuronally.

Deletion of SERF2 in mice delays embryonic development and alters amyloid deposit structure in the brain.

In age-related neurodegenerative diseases, like Alzheimer's and Parkinson's, disease-specific proteins become aggregation-prone and form amyloid-like deposits. Depletion of SERF proteins ameliorates this toxic process in worm and human cell models for diseases. Whether SERF modifies amyloid pathology in mammalian brain, however, has remained unknown.

A sudden collapse: the disaggregation of amyloid fibres.

A hallmark of age-related neurodegenerative diseases is the presence of highly stable protein aggregates, also known as amyloid fibres. As these fibres are strongly associated with disease, it is thought that clearance of these fibres could delay or prevent disease progression. In this issue of The EMBO Journal, Beton et al unravel how the Hsc70/DNAJB1/Apg2 disaggregase machinery disassembles amyloid fibres, using α-synuclein fibrils implicated in Parkinson's Disease as a model substrate.

Comparative Studies in the A30P and A53T α-Synuclein Strains to Investigate the Molecular Origins of Parkinson's Disease.

The aggregation of α-synuclein is a hallmark of Parkinson's disease (PD) and a variety of related neurological disorders. A number of mutations in this protein, including A30P and A53T, are associated with familial forms of the disease. Patients carrying the A30P mutation typically exhibit a similar age of onset and symptoms as sporadic PD, while those carrying the A53T mutation generally have an earlier age of onset and an accelerated progression.

Regulation of Age-Related Protein Toxicity.

Proteome damage plays a major role in aging and age-related neurodegenerative diseases. Under healthy conditions, molecular quality control mechanisms prevent toxic protein misfolding and aggregation. These mechanisms include molecular chaperones for protein folding, spatial compartmentalization for sequestration, and degradation pathways for the removal of harmful proteins.

Observation of an α-synuclein liquid droplet state and its maturation into Lewy body-like assemblies.

Misfolded α-synuclein is a major component of Lewy bodies, which are a hallmark of Parkinson's disease (PD). A large body of evidence shows that α-synuclein can aggregate into amyloid fibrils, but the relationship between α-synuclein self-assembly and Lewy body formation remains unclear. Here, we show, both in vitro and in a Caenorhabditis elegans model of PD, that α-synuclein undergoes liquid‒liquid phase separation by forming a liquid droplet state, which converts into an amyloid-rich hydrogel with Lewy-body-like properties.

Assessing motor-related phenotypes of Caenorhabditis elegans with the wide field-of-view nematode tracking platform.

Caenorhabditis elegans is a valuable model organism in biomedical research that has led to major discoveries in the fields of neurodegeneration, cancer and aging. Because movement phenotypes are commonly used and represent strong indicators of C. elegans fitness, there is an increasing need to replace manual assessments of worm motility with automated measurements to increase throughput and minimize observer biases.

Saved by the Matrix: UPR Independent Survival under ER Stress.

Cells are protected from endoplasmic reticulum stress through the unfolded protein response (UPR). In this issue of Cell, Schinzel, Higuchi-Sanabria, Shalem et al., identify a mechanism that helps cells cope with ER stress but is independent of canonical UPR activation, instead involving the extracellular matrix hyaluronidase, TMEM2, as a signaling mediator.

Age- and disease-specific changes of the kynurenine pathway in Parkinson's and Alzheimer's disease.

The kynurenine (Kyn) pathway, which regulates neuroinflammation and N-methyl-d-aspartate receptor activation, is implicated in Parkinson's disease (PD) and Alzheimer's disease (AD). Age-related changes in Kyn metabolism and altered cerebral Kyn uptake along large neutral amino acid transporters, could contribute to these diseases. To gain further insight into the role and prognostic potential of the Kyn pathway in PD and AD, we investigated systemic and cerebral Kyn metabolite production and estimations of their transporter-mediated uptake in the brain.

Fast Fluorescence Lifetime Imaging Reveals the Aggregation Processes of α-Synuclein and Polyglutamine in Aging .

The nematode worm has emerged as an important model organism in the study of the molecular mechanisms of protein misfolding diseases associated with amyloid formation because of its small size, ease of genetic manipulation, and optical transparency. Obtaining a reliable and quantitative read-out of protein aggregation in this system, however, remains a challenge. To address this problem, we here present a fast time-gated fluorescence lifetime imaging (TG-FLIM) method and show that it provides functional insights into the process of protein aggregation in living animals by enabling the rapid characterization of different types of aggregates.

Transcriptomics-Based Screening Identifies Pharmacological Inhibition of Hsp90 as a Means to Defer Aging.

Aging strongly influences human morbidity and mortality. Thus, aging-preventive compounds could greatly improve our health and lifespan. Here we screened for such compounds, known as geroprotectors, employing the power of transcriptomics to predict biological age.

C. elegans as a Model for Synucleinopathies and Other Neurodegenerative Diseases: Tools and Techniques.

Caenorhabditis elegans is widely used to investigate biological processes related to health and disease. Multiple C. elegans models for human neurodegenerative diseases do exist, including those expressing human α-synuclein.

Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond.

L-Tryptophan (Trp) metabolism through the kynurenine pathway (KP) is involved in the regulation of immunity, neuronal function and intestinal homeostasis. Imbalances in Trp metabolism in disorders ranging from cancer to neurodegenerative disease have stimulated interest in therapeutically targeting the KP, particularly the main rate-limiting enzymes indoleamine-2,3-dioxygenase 1 (IDO1), IDO2 and tryptophan-2,3-dioxygenase (TDO) as well as kynurenine monooxygenase (KMO). However, although small-molecule IDO1 inhibitors showed promise in early-stage cancer immunotherapy clinical trials, a phase III trial was negative.

Automated Behavioral Analysis of Large C. elegans Populations Using a Wide Field-of-view Tracking Platform.

Caenorhabditis elegans is a well-established animal model in biomedical research, widely employed in functional genomics and ageing studies. To assess the health and fitness of the animals under study, one typically relies on motility readouts, such as the measurement of the number of body bends or the speed of movement. These measurements usually involve manual counting, making it challenging to obtain good statistical significance, as time and labor constraints often limit the number of animals in each experiment to 25 or less.

Nuclear/Cytoplasmic Fractionation of Proteins from .

is widely used to investigate biological processes related to health and disease. To study protein localization, fluorescently-tagged proteins can be used or immunohistochemistry can be performed in whole worms. Here, we describe a technique to localize a protein of interest at a subcellular level in lysates, which can give insight into the location, function and/or toxicity of proteins.

Filter Retardation Assay for Detecting and Quantifying Polyglutamine Aggregates Using Lysates.

Protein aggregation is a hallmark of several neurodegenerative diseases and is associated with impaired protein homeostasis. This imbalance is caused by the loss of the protein's native conformation, which ultimately results in its aggregation or abnormal localization within the cell. Using a model of polyglutamine diseases, we describe in detail the filter retardation assay, a method that captures protein aggregates in a cellulose acetate membrane and allows its detection and quantification by immunoblotting.

Multistep Inhibition of α-Synuclein Aggregation and Toxicity in Vitro and in Vivo by Trodusquemine.

The aggregation of α-synuclein, an intrinsically disordered protein that is highly abundant in neurons, is closely associated with the onset and progression of Parkinson's disease. We have shown previously that the aminosterol squalamine can inhibit the lipid induced initiation process in the aggregation of α-synuclein, and we report here that the related compound trodusquemine is capable of inhibiting not only this process but also the fibril-dependent secondary pathways in the aggregation reaction. We further demonstrate that trodusquemine can effectively suppress the toxicity of α-synuclein oligomers in neuronal cells, and that its administration, even after the initial growth phase, leads to a dramatic reduction in the number of α-synuclein inclusions in a Caenorhabditis elegans model of Parkinson's disease, eliminates the related muscle paralysis, and increases lifespan.