Protein with Tau-like repeats (PTL-1) modulates the oxidative stress response, neuronal ageing and lifespan

Protein with Tau-like repeats (PTL-1) is the sole Tau /MAP2/MAP4 homolog in Caenorhabditis elegans. Dysregulation of Tau is a pathological hallmark of neurodegenerative diseases such as Alzheimer’s disease. Therefore, reducing Tau levels has been suggested as a therapeutic strategy. We used PTL-1 to model the biological functions of a Tau-like protein without the complication of functional redundancy. Firstly, our data indicate that PTL-1 in the nervous system mediates the oxidative stress response in a pathway that may involve the C. elegans homolog of the Nrf2 transcription factor, SKN-1. In addition, we found that ptl-1 mutant animals are short-lived, and that lifespan modulation by PTL-1 may occur via similar processes to those mediated by SKN-1. We also observed that the short-lived phenotype of ptl-1 mutants can be rescued by transgenic re-expression of PTL-1 but not human Tau. Secondly, we show that PTL-1 maintains the structural integrity of neurons with increasing age. This phenotype observed in ptl-1 mutant animals could again be rescued by PTL-1 re-expression but not by human Tau. Thirdly, our data also indicate that the regulation of neuronal ageing by PTL-1 is cell-autonomous. We expressed PTL-1 in touch neurons and showed rescue of the neuronal ageing phenotype of ptl-1 mutant animals in these neurons but not in another neuronal subset. Knockdown of PTL-1 specifically in touch neurons also resulted in premature neuronal ageing in these neurons but not in a distinct subset of neurons, further supporting the conclusion that PTL-1 functions in a cell-autonomous manner. Interestingly, we showed that expression of PTL-1 in touch neurons alone was unable to rescue the shortened lifespan observed in null mutants, indicating that premature neuronal ageing in touch neurons and organismal ageing can be decoupled. Our data show that PTL-1 in C. elegans is a useful model to investigate the physiological functions of a Tau-like protein. Overall, our findings that PTL-1 is involved in the stress response, neuronal ageing and lifespan modulation suggest that some of the effects of Tau pathology may result from the loss of physiological Tau functions and not solely from a toxic gain-of-function due to an accumulation of Tau

Protein with Tau-like repeats (PTL-1) modulates the oxidative stress response, neuronal ageing and lifespan

Protein with Tau-like repeats (PTL-1) is the sole Tau /MAP2/MAP4 homolog in Caenorhabditis elegans. Dysregulation of Tau is a pathological hallmark of neurodegenerative diseases such as Alzheimer’s disease. Therefore, reducing Tau levels has been suggested as a therapeutic strategy. We used PTL-1 to model the biological functions of a Tau-like protein without the complication of functional redundancy. Firstly, our data indicate that PTL-1 in the nervous system mediates the oxidative stress response in a pathway that may involve the C. elegans homolog of the Nrf2 transcription factor, SKN-1. In addition, we found that ptl-1 mutant animals are short-lived, and that lifespan modulation by PTL-1 may occur via similar processes to those mediated by SKN-1. We also observed that the short-lived phenotype of ptl-1 mutants can be rescued by transgenic re-expression of PTL-1 but not human Tau. Secondly, we show that PTL-1 maintains the structural integrity of neurons with increasing age. This phenotype observed in ptl-1 mutant animals could again be rescued by PTL-1 re-expression but not by human Tau. Thirdly, our data also indicate that the regulation of neuronal ageing by PTL-1 is cell-autonomous. We expressed PTL-1 in touch neurons and showed rescue of the neuronal ageing phenotype of ptl-1 mutant animals in these neurons but not in another neuronal subset. Knockdown of PTL-1 specifically in touch neurons also resulted in premature neuronal ageing in these neurons but not in a distinct subset of neurons, further supporting the conclusion that PTL-1 functions in a cell-autonomous manner. Interestingly, we showed that expression of PTL-1 in touch neurons alone was unable to rescue the shortened lifespan observed in null mutants, indicating that premature neuronal ageing in touch neurons and organismal ageing can be decoupled. Our data show that PTL-1 in C. elegans is a useful model to investigate the physiological functions of a Tau-like protein. Overall, our findings that PTL-1 is involved in the stress response, neuronal ageing and lifespan modulation suggest that some of the effects of Tau pathology may result from the loss of physiological Tau functions and not solely from a toxic gain-of-function due to an accumulation of Tau

Amyotrophic Lateral Sclerosis: Proteins, Proteostasis, Prions, and Promises

Copyright 2020 McAlary, Chew, Lum, Geraghty, Yerbury and Cashman. Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of the motor neurons that innervate muscle, resulting in gradual paralysis and culminating in the inability to breathe or swallow. This neuronal degeneration occurs in a spatiotemporal manner from a point of onset in the central nervous system (CNS), suggesting that there is a molecule that spreads from cell-to-cell. There is strong evidence that the onset and progression of ALS pathology is a consequence of protein misfolding and aggregation. In line with this, a hallmark pathology of ALS is protein deposition and inclusion formation within motor neurons and surrounding glia of the proteins TAR DNA-binding protein 43, superoxide dismutase-1, or fused in sarcoma. Collectively, the observed protein aggregation, in conjunction with the spatiotemporal spread of symptoms, strongly suggests a prion-like propagation of protein aggregation occurs in ALS. In this review, we discuss the role of protein aggregation in ALS concerning protein homeostasis (proteostasis) mechanisms and prion-like propagation. Furthermore, we examine the experimental models used to investigate these processes, including in vitro assays, cultured cells, invertebrate models, and murine models. Finally, we evaluate the therapeutics that may best prevent the onset or spread of pathology in ALS and discuss what lies on the horizon for treating this currently incurable disease

Caenorhabditis elegans and the network control framework-FAQs.

Control is essential to the functioning of any neural system. Indeed, under healthy conditions the brain must be able to continuously maintain a tight functional control between the system's inputs and outputs. One may therefore hypothesize that the brain's wiring is predetermined by the need to maintain control across multiple scales, maintaining the stability of key internal variables, and producing behaviour in response to environmental cues. Recent advances in network control have offered a powerful mathematical framework to explore the structure-function relationship in complex biological, social and technological networks, and are beginning to yield important and precise insights on neuronal systems. The network control paradigm promises a predictive, quantitative framework to unite the distinct datasets necessary to fully describe a nervous system, and provide mechanistic explanations for the observed structure and function relationships. Here, we provide a thorough review of the network control framework as applied to Caenorhabditis elegans (Yan et al. 2017 Nature550, 519-523. (doi:10.1038/nature24056)), in the style of Frequently Asked Questions. We present the theoretical, computational and experimental aspects of network control, and discuss its current capabilities and limitations, together with the next likely advances and improvements. We further present the Python code to enable exploration of control principles in a manner specific to this prototypical organism.This article is part of a discussion meeting issue 'Connectome to behaviour: modelling C. elegans at cellular resolution'

The Multilayer Connectome of Caenorhabditis elegans.

Connectomics has focused primarily on the mapping of synaptic links in the brain; yet it is well established that extrasynaptic volume transmission, especially via monoamines and neuropeptides, is also critical to brain function and occurs primarily outside the synaptic connectome. We have mapped the putative monoamine connections, as well as a subset of neuropeptide connections, in C. elegans based on new and published gene expression data. The monoamine and neuropeptide networks exhibit distinct topological properties, with the monoamine network displaying a highly disassortative star-like structure with a rich-club of interconnected broadcasting hubs, and the neuropeptide network showing a more recurrent, highly clustered topology. Despite the low degree of overlap between the extrasynaptic (or wireless) and synaptic (or wired) connectomes, we find highly significant multilink motifs of interaction, pinpointing locations in the network where aminergic and neuropeptide signalling modulate synaptic activity. Thus, the C. elegans connectome can be mapped as a multiplex network with synaptic, gap junction, and neuromodulator layers representing alternative modes of interaction between neurons. This provides a new topological plan for understanding how aminergic and peptidergic modulation of behaviour is achieved by specific motifs and loci of integration between hard-wired synaptic or junctional circuits and extrasynaptic signals wirelessly broadcast from a small number of modulatory neurons

SEABED INFRASTRUCTURE DEFENSE ANALYSIS

Traditional fleet operations and technologies are not adequately suited to counter the growing threat to undersea infrastructure from autonomous undersea systems. A cost-effective unmanned and manned system of systems is required to provide defense of this seabed infrastructure. This paper proposes possible system architectures to defend against this emerging threat to include passive barriers and active defense systems. The effectiveness of those candidate systems is evaluated through multiple agent-based modeling simulations of UUV versus UUV engagements. Analysis resulted in two major findings. First, point defense of critical assets is more effective than barrier defense. Second, system design must focus on minimizing the time required to effectively engage and neutralize threats, either through improvement to defensive UUV speed or investment in more UUV docking stations and sensor arrays. Cost analysis suggests that acquisition and operations cost of the recommended defensive system is less than the projected financial impact of a successful attack.http://archive.org/details/seabedinfrastruc1094562767Lieutenant, United States NavyLieutenant, United States NavyLieutenant, United States NavyMajor, Israel Defence ForcesMajor, Republic of Singapore Air ForceMajor, Republic of Singapore Air ForceCaptain, Singapore ArmyLieutenant, United States NavyLieutenant, United States NavyLieutenant, United States NavyMajor, Republic of Singapore Air ForceCaptain, Singapore ArmyCivilian, Ministry of Defense, SingaporeLieutenant, United States NavyLieutenant Commander, United States NavyLieutenant Junior Grade, United States NavyCivilian, Ministry of Defense, SingaporeCivilian, Ministry of Defense, SingaporeMajor, Republic of Singapore Air ForceMajor, United States Marine CorpsMajor, Singapore ArmyApproved for public release; distribution is unlimited

Early and mid-career scientists face a bleak future in the wake of the pandemic

The COVID-19 pandemic has taken a heavy toll on research in Australia. We surveyed 333 early and mid-career researchers in science, technical, engineering and medical (STEM) fields and found the impact on their productivity and mental health has been dire, with many considering leaving research altogether

Identification of a conserved, orphan G-protein coupled receptor required for efficient pathogen clearance in <i>C. elegans</i>

G-protein coupled receptors contribute to host defense across the animal kingdom, transducing many signals involved in both vertebrate and invertebrate immune responses. Whilst it has become well established that the nematode worm Caenorhabditis elegans triggers innate immune responses following infection with numerous bacterial, fungal and viral pathogens, the mechanisms by which C. elegans recognises these pathogens have remained somewhat more elusive. C. elegans G-protein coupled receptors have been implicated in recognising pathogen-associated damage and activating downstream host immune responses. Here we identify and characterise a novel G-protein coupled receptor required to regulate the C. elegans response to infection with Microbacterium nematophilum. We show that this receptor, which we designate PCDR-1, is required for efficient pathogen clearance following infection. PCDR-1 acts upstream of multiple G-proteins including the C. elegans Gαq ortholog EGL-30 in rectal epithelial cells to promote pathogen clearance via a novel mechanism