scholarly journals Genetic and pharmacological interventions in the aging motor nervous system slow motor aging and extend life span inC. elegans

2019 ◽  
Vol 5 (1) ◽  
pp. eaau5041 ◽  
Author(s):  
Guang Li ◽  
Jianke Gong ◽  
Jie Liu ◽  
Jinzhi Liu ◽  
Huahua Li ◽  
...  
Keyword(s):  
Nervous System ◽  
Life Span ◽  
Motor Neurons ◽  
Neuromuscular Junctions ◽  
Functional Decline ◽  
Bk Channel ◽  
Pharmacological Interventions ◽  
Genetic Ablation ◽  
Extend Life Span ◽  
Age Dependent

As animals and humans age, the motor system undergoes a progressive functional decline, leading to frailty. Age-dependent functional deteriorations at neuromuscular junctions (NMJs) contribute to this motor aging. However, it is unclear whether one can intervene in this process to slow motor aging. TheCaenorhabditis elegansBK channel SLO-1 dampens synaptic transmission at NMJs by repressing synaptic release from motor neurons. Here, we show that genetic ablation of SLO-1 not only reduces the rate of age-dependent motor activity decline to slow motor aging but also surprisingly extends life span. SLO-1 acts in motor neurons to mediate both functions. Genetic knockdown or pharmacological inhibition of SLO-1 in aged, but not young, worms can slow motor aging and prolong longevity. Our results demonstrate that genetic and pharmacological interventions in the aging motor nervous system can promote both health span and life span.

scholarly journals Short-term enhancement of motor neuron synaptic exocytosis during early aging extends lifespan in Caenorhabditis elegans

2020 ◽  
Vol 245 (17) ◽  
pp. 1552-1559
Author(s):  
Tsui-Ting Ching ◽  
Yen-Chieh Chen ◽  
Guang Li ◽  
Jianfeng Liu ◽  
X Z Shawn Xu ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Neuromuscular Junctions ◽  
Early Stage ◽  
Functional Decline ◽  
The Elderly ◽  
Term Treatment ◽  
Short Term ◽  
Short Term Treatment ◽  
C Elegans ◽  
Synaptic Exocytosis

Age-related mobility decline is often associated with negative physical and psychological outcomes, such as frailty, in the elderly population. In C. elegans, during the early stage of the aging process, a progressive deficit of synaptic exocytosis in the motor neurons results in a functional decline at the neuromuscular junctions, which eventually leads to degeneration of both neurons and muscles. This age-dependent functional decline can be ameliorated by pharmacological interventions, such as arecoline, a muscarinic AChR agonist known to promote synaptic exocytosis at the neuromuscular junctions. In this study, we found that a short-term treatment of arecoline during the early stage of aging, when the NMJ functional decline begins, not only slows muscle tissue aging, but also extends lifespan in C. elegans. We have also demonstrated that arecoline acts on the GAR-2/PLCβ pathway in the motor neurons to increases longevity. Together, our findings suggest that synaptic transmission in aging motor neurons may serve as a potential target for pharmacological interventions to promote both health span and lifespan, when applied at the early stage aging. Impact statement The functional decline of motor activity is a common feature in almost all aging animals that leads to frailty, loss of independence, injury, and even death in the elderly population. Thus, understanding the molecular mechanism that drives the initial stage of this functional decline and developing strategies to increase human healthspan and even lifespan by targeting this process would be of great interests to the field. In this study, we found that by precisely targeting the motor neurons to potentiate its synaptic releases either genetically or pharmacologically, we can not only delay the functional aging at NMJs but also slow the rate of aging at the organismal level. Most importantly, we have demonstrated that a critical window of time, that is the early stage of NMJs functional decline, is required for the beneficial effects. A short-term treatment within this time period is sufficient to extend the animals’ lifespan.

Collagen Response and Glycoprotein VI Function Decline Progressively as Canine Platelets Age in vivo

2002 ◽  
Vol 88 (09) ◽  
pp. 510-516 ◽  
Author(s):  
L. Alberio ◽  
P. Friese ◽  
K. J. Clemetson ◽  
G. L. Dale
Keyword(s):  
Life Span ◽  
Functional Decline ◽  
Progressive Increase ◽  
Cell Aging ◽  
Platelet Response ◽  
Glycoprotein Vi ◽  
Cell Age ◽  
Age Dependent ◽  
Normal Life Span

SummaryClinical and experimental observations suggest that platelet function deteriorates quickly with cell age. However, efforts to define agedependent alterations have detected only modest biochemical changes occurring late in the cell life span. In this report, we demonstrate two significant alterations of the collagen response occurring during in vivo aging of canine platelets: a progressive increase in the EC50 for collagen types I, III and V and the emergence of a population of aged platelets which are refractory to collagen. Experiments with convulxin, a specific agonist for the collagen receptor glycoprotein VI (GPVI), also demonstrate an age-dependent decline in activation and the appearance of a non-reactive, aged population as observed with native collagens. Our studies indicate that canine platelets have two distinct binding levels for FITC-labeled convulxin and that the higher binding level disappears upon cell aging. During these studies one dog (#428) was identified whose platelets not only failed to demonstrate an age-dependent decrease in convulxin reactivity but also maintained a high convulxinbinding ability throughout their otherwise normal life span. Transfusion of biotinylated platelets from control dogs into dog #428 showed that the expected changes in collagen response and GPVI function did not occur in the transfused platelets. These observations demonstrate that the canine platelet response towards collagen is strongly dependent upon cell-age and suggest that this functional decline is at least partly due to an extrinsic-mediated alteration, possibly proteolytic, of GPVI.This work was supported in part by grants HL53585 and HL68129 from the National Institutes of Health (GLD) and the Swiss National Science Foundation (SSMBS grant, LA; grant 31-52396.97, KJC). This work has been presented at the XVIII Congress of the International Society on Thrombosis and Haemostasis (Paris, 2001).

The Circuit for Chemotaxis and Exploratory Behavior in Caenorhabditis Elegans

2017 ◽  
pp. 369-376
Author(s):  
Cornelia I. Bargmann
Keyword(s):  
Nervous System ◽  
Caenorhabditis Elegans ◽  
Sensory Neurons ◽  
Motor Neurons ◽  
Neuromuscular Junctions ◽  
Wiring Diagram ◽  
C Elegans ◽  
Section Electron ◽  
Adult Hermaphrodite ◽  
Electrophysiological Characterization

A wiring diagram of the Caenorhabditis elegans nervous system was constructed from serial-section electron micrographs 30 years ago. This wiring diagram divides the 302 neurons in the nervous system of the adult hermaphrodite into three overall classes: sensory neurons, motor neurons that form neuromuscular junctions, and interneurons that connect sensory neurons with motor neurons. Most sensory neurons and interneurons belong to bilaterally symmetric pairs with similar connections and morphologies, while motor neurons belong to larger classes. The C. elegans nervous system presents an exceptional situation in which neuroanatomical connections are extremely well defined and reproducible among animals. These detailed anatomical studies and a parallel genetic attack have increasingly been joined by functional and electrophysiological characterization.

Effects of Hyperoxia on Lung Utrastructure

1970 ◽  
Vol 28 ◽  
pp. 26-27
Author(s):  
Gladys Harrison
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Light Microscopy ◽  
Oxygen Effects ◽  
Age Dependent ◽  
The Central Nervous System ◽  
The Subject ◽  
Space Age ◽  
Alveolar Septa ◽  
Extensive Damage

With the advent of the space age and the need to determine the requirements for a space cabin atmosphere, oxygen effects came into increased importance, even though these effects have been the subject of continuous research for many years. In fact, Priestly initiated oxygen research when in 1775 he published his results of isolating oxygen and described the effects of breathing it on himself and two mice, the only creatures to have had the “privilege” of breathing this “pure air”.Early studies had demonstrated the central nervous system effects at pressures above one atmosphere. Light microscopy revealed extensive damage to the lungs at one atmosphere. These changes which included perivascular and peribronchial edema, focal hemorrhage, rupture of the alveolar septa, and widespread edema, resulted in death of the animal in less than one week. The severity of the symptoms differed between species and was age dependent, with young animals being more resistant.

Co-Culture of ES Cell-Derived Motor Neurons and Myotubes Show the Formation of Neuromuscular Junctions and Changes in Gene Expression

2006 ◽  
Vol 22 (06) ◽  
Author(s):  
Aleid Ruijs ◽  
Tateki Kubo ◽  
Jae Song ◽  
Milan Ranka ◽  
Mark Randolph ◽  
...  
Keyword(s):  
Gene Expression ◽  
Motor Neurons ◽  
Neuromuscular Junctions ◽  
Es Cell

The Yin and Yang of BK Channels in Epilepsy

2018 ◽  
Vol 17 (4) ◽  
pp. 272-279 ◽  
Author(s):  
Yudan Zhu ◽  
Shuzhang Zhang ◽  
Yijun Feng ◽  
Qian Xiao ◽  
Jiwei Cheng ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Bk Channels ◽  
Bk Channel ◽  
Potential Shape ◽  
Yin And Yang ◽  
The Central Nervous System ◽  
Action Potential Shape ◽  
Excitability Of Neurons

Background & Objective: The large conductance calcium-activated potassium (BK) channel, extensively distributed in the central nervous system (CNS), is considered as a vital player in the pathogenesis of epilepsy, with evidence implicating derangement of K+ as well as regulating action potential shape and duration. However, unlike other channels implicated in epilepsy whose function in neurons could clearly be labeled “excitatory” or “inhibitory”, the unique physiological behavior of the BK channel allows it to both augment and decrease the excitability of neurons. Thus, the role of BK in epilepsy is controversial so far, and a growing area of intense investigation. Conclusion: Here, this review aims to highlight recent discoveries on the dichotomous role of BK channels in epilepsy, focusing on relevant BK-dependent pro- as well as antiepileptic pathways, and discuss the potential of BK specific modulators for the treatment of epilepsy.

scholarly journals Current Knowledge of Endolysosomal and Autophagy Defects in Hereditary Spastic Paraplegia

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1678
Author(s):  
Liriopé Toupenet Marchesi ◽  
Marion Leblanc ◽  
Giovanni Stevanin
Keyword(s):  
Nervous System ◽  
Motor Neurons ◽  
Neurological Disorders ◽  
Hereditary Spastic Paraplegia ◽  
Current Knowledge ◽  
Spastic Paraplegia ◽  
Functional Convergence ◽  
The Common ◽  
Hsp Genes

Hereditary spastic paraplegia (HSP) refers to a group of neurological disorders involving the degeneration of motor neurons. Due to their clinical and genetic heterogeneity, finding common effective therapeutics is difficult. Therefore, a better understanding of the common pathological mechanisms is necessary. The role of several HSP genes/proteins is linked to the endolysosomal and autophagic pathways, suggesting a functional convergence. Furthermore, impairment of these pathways is particularly interesting since it has been linked to other neurodegenerative diseases, which would suggest that the nervous system is particularly sensitive to the disruption of the endolysosomal and autophagic systems. In this review, we will summarize the involvement of HSP proteins in the endolysosomal and autophagic pathways in order to clarify their functioning and decipher some of the pathological mechanisms leading to HSP.

scholarly journals Functional Neuromuscular Junctions Formed by Embryonic Stem Cell-Derived Motor Neurons

PLoS ONE ◽  
2012 ◽  
Vol 7 (5) ◽  
pp. e36049 ◽  
Author(s):  
Joy A. Umbach ◽  
Katrina L. Adams ◽  
Cameron B. Gundersen ◽  
Bennett G. Novitch
Keyword(s):  
Stem Cell ◽  
Embryonic Stem Cell ◽  
Motor Neurons ◽  
Neuromuscular Junctions ◽  
Embryonic Stem

Retinoid-binding protein distribution in the developing mammalian nervous system

Development ◽  
1990 ◽  
Vol 109 (1) ◽  
pp. 75-80 ◽  
Author(s):  
M. Maden ◽  
D.E. Ong ◽  
F. Chytil
Keyword(s):  
Nervous System ◽  
Retinoic Acid ◽  
Neural Crest ◽  
Motor Neurons ◽  
Neural Tube ◽  
Binding Protein ◽  
Sympathetic Ganglia ◽  
Retinol Binding Protein ◽  
Otic Vesicle ◽  
Protein Distribution

We have analysed the distribution of cellular retinol-binding protein (CRBP) and cellular retinoic acid-binding protein (CRABP) in the day 8.5-day 12 mouse and rat embryo. CRBP is localised in the heart, gut epithelium, notochord, otic vesicle, sympathetic ganglia, lamina terminalis of the brain, and, most strikingly, in a ventral stripe across the developing neural tube in the future motor neuron region. This immunoreactivity remains in motor neurons and, at later stages, motor axons are labelled in contrast to unlabelled sensory axons. CRABP is localised to the neural crest cells, which are particularly noticeable streaming into the branchial arches. At later stages, neural crest derivatives such as Schwann cells, cells in the gut wall and sympathetic ganglia are immunoreactive. An additional area of CRABP-positive cells are neuroblasts in the mantle layer of the neural tube, which subsequently appear to be the axons and cell bodies of the commissural system. Since retinol and retinoic acid are the endogenous ligands for these binding proteins, we propose that retinoids may play a role in the development and differentiation of the mammalian nervous system and may interact with certain homoeobox genes whose transcripts have also been localised within the nervous system.

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