scholarly journals Partial Inhibition of Calcineurin Activity by Rcn2 as a Potential Remedy for Vps13 Deficiency

2021 ◽  
Vol 22 (3) ◽  
pp. 1193
Author(s):  
Patrycja Wardaszka ◽  
Piotr Soczewka ◽  
Marzena Sienko ◽  
Teresa Zoladek ◽  
Joanna Kaminska
Keyword(s):  
Neurodegenerative Disorders ◽  
Neurological Diseases ◽  
Therapeutic Strategies ◽  
Negative Regulator ◽  
Site Directed Mutagenesis ◽  
Yeast Cells ◽  
Negative Effects ◽  
Catalytic Subunits ◽  
Calcineurin Activity ◽  
Potential Remedy

Regulation of calcineurin, a Ca2+/calmodulin-regulated phosphatase, is important for the nervous system, and its abnormal activity is associated with various pathologies, including neurodegenerative disorders. In yeast cells lacking the VPS13 gene (vps13Δ), a model of VPS13-linked neurological diseases, we recently demonstrated that calcineurin is activated, and its downregulation reduces the negative effects associated with vps13Δ mutation. Here, we show that overexpression of the RCN2 gene, which encodes a negative regulator of calcineurin, is beneficial for vps13Δ cells. We studied the molecular mechanism underlying this effect through site-directed mutagenesis of RCN2. The interaction of the resulting Rcn2 variants with a MAPK kinase, Slt2, and subunits of calcineurin was tested. We show that Rcn2 binds preferentially to Cmp2, one of two alternative catalytic subunits of calcineurin, and partially inhibits calcineurin. Rcn2 ability to bind to and reduce the activity of calcineurin was important for the suppression. The binding of Rcn2 to Cmp2 requires two motifs in Rcn2: the previously characterized C-terminal motif and a new N-terminal motif that was discovered in this study. Altogether, our findings can help to better understand calcineurin regulation and to develop new therapeutic strategies against neurodegenerative diseases based on modulation of the activity of selected calcineurin isoforms.

The Effects of P75NTR on Learning Memory Mediated by Hippocampal Apoptosis and Synaptic Plasticity

2020 ◽  
Vol 26 ◽  
Author(s):  
Jun-Jie Tang ◽  
Shuang Feng ◽  
Xing-Dong Chen ◽  
Hua Huang ◽  
Min Mao ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Learning And Memory ◽  
Neurological Diseases ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor ◽  
Negative Effects ◽  
Apoptotic Effect ◽  
New Ideas ◽  
The Relationship

: Neurological diseases bring great mental and physical torture to the patients, and have long-term and sustained negative effects on families and society. The attention to neurological diseases is increasing, and the improvement of the material level is accompanied by an increase in the demand for mental level. The p75 neurotrophin receptor (p75NTR) is a low-affinity neurotrophin receptor and involved in diverse and pleiotropic effects in the developmental and adult central nervous system (CNS). Since neurological diseases are usually accompanied by the regression of memory, the pathogenesis of p75NTR also activates and inhibits other signaling pathways, which has a serious impact on the learning and memory of patients. The results of studies shown that p75NTR is associated with LTP/LTD-induced synaptic enhancement and inhibition, suggest that p75NTR may be involved in the progression of synaptic plasticity. And its pro-apoptotic effect is associated with activation of proBDNF and inhibition of proNGF, and TrkA/p75NTR imbalance leads to pro-survival or pro-apoptotic phenomena. It can be inferred that p75NTR mediates apoptosis in the hippocampus and amygdale, which may affect learning and memory behavior. This article mainly discusses the relationship between p75NTR and learning memory and associated mechanisms, which may provide some new ideas for the treatment of neurological diseases.

scholarly journals Human Monocytes Plasticity in Neurodegeneration

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 717
Author(s):  
Ilenia Savinetti ◽  
Angela Papagna ◽  
Maria Foti
Keyword(s):  
Neurodegenerative Disorders ◽  
Current Knowledge ◽  
Neurological Diseases ◽  
Surface Marker ◽  
First Line ◽  
Surface Marker Expression ◽  
Physiological Properties ◽  
Attractive Therapeutic Target ◽  
The Brain ◽  
Lateral Sclerosis

Monocytes play a crucial role in immunity and tissue homeostasis. They constitute the first line of defense during the inflammatory process, playing a role in the pathogenesis and progression of diseases, making them an attractive therapeutic target. They are heterogeneous in morphology and surface marker expression, which suggest different molecular and physiological properties. Recent evidences have demonstrated their ability to enter the brain, and, as a consequence, their hypothetical role in different neurodegenerative diseases. In this review, we will discuss the current knowledge about the correlation between monocyte dysregulation in the brain and/or in the periphery and neurological diseases in humans. Here we will focus on the most common neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and multiple sclerosis.

scholarly journals The status of neurology fellowships in the United States: clinical needs, educational barriers, and future outlooks

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Harini Sarva ◽  
Gustavo A. Patino ◽  
Mehmood Rashid ◽  
James W. M. Owens ◽  
Matthew S. Robbins ◽  
...  
Keyword(s):  
United States ◽  
American Academy ◽  
Neurodegenerative Disorders ◽  
Disease Burden ◽  
Neurological Diseases ◽  
The United States ◽  
Educational Barriers ◽  
The Status

AbstractThe need for subspecialty-trained neurologists is growing in parallel with increasing disease burden. However, despite the immense burden of neurological diseases, like headache and neurodegenerative disorders, recruitment into these subspecialties remains insufficient in the United States. In this manuscript, a group of educators from the American Academy of Neurology’s A.B. Baker Section on Neurological Education sought to review and discuss the current landscape of neurology fellowships in the United States, the factors driving fellowship recruitment and the educational barriers. Moreover, suggestions to potentially improve recruitment for under-selected fellowships, which can contribute towards an alignment between neurological education and neurological needs, and future educational scenarios are discussed.

scholarly journals Opposing functions of the plant TOPLESS gene family during SNC1-mediated autoimmunity

2020 ◽  
Author(s):  
Christopher M. Garner ◽  
Benjamin J. Spears ◽  
Jianbin Su ◽  
Leland Cseke ◽  
Samantha N. Smith ◽  
...  
Keyword(s):  
Immune System ◽  
Genetic Interaction ◽  
Plant Immunity ◽  
Family Members ◽  
Negative Regulator ◽  
Careful Study ◽  
Negative Effects ◽  
Activating Mutations ◽  
Immune Receptors ◽  
Regulatory Processes

AbstractRegulation of the plant immune system is important for controlling the specificity and amplitude of responses to pathogens and in preventing growth-inhibiting autoimmunity that leads to reductions in plant fitness. In previous work, we reported that SRFR1, a negative regulator of effector-triggered immunity, interacts with SNC1 and EDS1. When SRFR1 is non-functional in the Arabidopsis accession Col-0, SNC1 levels increase, causing a cascade of events that lead to autoimmunity phenotypes. Previous work showed that some members of the transcriptional co-repressor family TOPLESS interact with SNC1 to repress negative regulators of immunity. Therefore, to explore potential connections between SRFR1 and TOPLESS family members, we took a genetic approach that examined the effect of each TOPLESS member in the srfr1 mutant background. The data indicated that an additive genetic interaction exists between SRFR1 and two members of the TOPLESS family, TPR2 and TPR3, as demonstrated by increased stunting and elevated PR2 expression in srfr1 tpr2 and srfr1 tpr2 tpr3 mutants. Furthermore, the tpr2 mutation intensifies autoimmunity in the auto-active snc1-1 mutant, indicating a novel role of these TOPLESS family members in negatively regulating SNC1-dependent phenotypes. This negative regulation can also be reversed by overexpressing TPR2 in the srfr1 tpr2 background. Thus, this work uncovers diverse functions of individual members of the TOPLESS family in Arabidopsis and provides evidence for the additive effect of transcriptional and post-transcriptional regulation of SNC1.Author SummaryThe immune system is a double-edged sword that affords organisms with protection against infectious diseases but can also lead to negative effects if not properly controlled. Plants only possess an innate antimicrobial immune system that relies on rapid upregulation of defenses once immune receptors detect the presence of microbes. Plant immune receptors known as resistance proteins play a key role in rapidly triggering defenses if pathogens breach other defenses. A common model of unregulated immunity in the reference Arabidopsis variety Columbia-0 involves a resistance gene called SNC1. When the SNC1 protein accumulates to unnaturally high levels or possesses auto-activating mutations, the visible manifestations of immune overactivity include stunted growth and low biomass and seedset. Consequently, expression of this gene and accumulation of the encoded protein are tightly regulated on multiple levels. Despite careful study the mechanisms of SNC1 gene regulation are not fully understood. Here we present data on members of the well-known TOPLESS family of transcriptional repressors. While previously characterized members were shown to function in indirect activation of defenses, TPR2 and TPR3 are shown here to function in preventing high defense activity. This study therefore contributes to the understanding of complex regulatory processes in plant immunity.

scholarly journals Kynurenines in chronic neurodegenerative disorders: future therapeutic strategies

2009 ◽  
Vol 116 (11) ◽  
pp. 1403-1409 ◽  
Author(s):  
D. Zádori ◽  
P. Klivényi ◽  
E. Vámos ◽  
F. Fülöp ◽  
J. Toldi ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Therapeutic Strategies

Identification of pre-mRNA polyadenylation sites in Saccharomyces cerevisiae

1992 ◽  
Vol 12 (9) ◽  
pp. 4215-4229
Author(s):  
S Heidmann ◽  
B Obermaier ◽  
K Vogel ◽  
H Domdey
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Signal Sequence ◽  
Site Directed Mutagenesis ◽  
Yeast Cells ◽  
Yeast Saccharomyces Cerevisiae ◽  
Adh1 Gene ◽  
Polyadenylation Sites ◽  
Yeast Genes

In contrast to higher eukaryotes, little is known about the nature of the sequences which direct 3'-end formation of pre-mRNAs in the yeast Saccharomyces cerevisiae. The hexanucleotide AAUAAA, which is highly conserved and crucial in mammals, does not seem to have any functional importance for 3'-end formation in yeast cells. Instead, other elements have been proposed to serve as signal sequences. We performed a detailed investigation of the yeast ACT1, ADH1, CYC1, and YPT1 cDNAs, which showed that the polyadenylation sites used in vivo can be scattered over a region spanning up to 200 nucleotides. It therefore seems very unlikely that a single signal sequence is responsible for the selection of all these polyadenylation sites. Our study also showed that in the large majority of mRNAs, polyadenylation starts directly before or after an adenosine residue and that 3'-end formation of ADH1 transcripts occurs preferentially at the sequence PyAAA. Site-directed mutagenesis of these sites in the ADH1 gene suggested that this PyAAA sequence is essential for polyadenylation site selection both in vitro and in vivo. Furthermore, the 3'-terminal regions of the yeast genes investigated here are characterized by their capacity to act as signals for 3'-end formation in vivo in either orientation.

Stem Cells from Human Exfoliated Deciduous Teeth and their Promise as Preventive and Therapeutic Strategies for Neurological Diseases and Injuries

2021 ◽  
Vol 17 ◽  
Author(s):  
Lingyi Huang ◽  
Zizhuo Zheng ◽  
Ding Bai ◽  
Xianglong Han
Keyword(s):  
Stem Cells ◽  
Potential Role ◽  
Neurological Diseases ◽  
Therapeutic Strategies ◽  
Deciduous Teeth ◽  
Research Attention ◽  
Considerable Potential ◽  
Prevention And Treatment ◽  
Human Exfoliated Deciduous Teeth

Abstract: Stem cells from human exfoliated deciduous teeth (SHEDs) are relatively easy to isolate from exfoliated deciduous teeth, which are obtained via dental therapy as biological waste. SHEDs originate from the embryonic neural crest and therefore have considerable potential for neurogenic differentiation. Currently, an increasing amount of research attention is focused on the therapeutic applications of SHEDs in neurological diseases and injuries. In this article, we summarize the biological characteristics of SHEDs and the potential role of SHEDs and their derivatives, including conditioned medium from SHEDs and the exosomes they secrete, in the prevention and treatment of neurological diseases and injuries.

Signals that produce 3' termini in CYC1 mRNA of the yeast Saccharomyces cerevisiae

1993 ◽  
Vol 13 (12) ◽  
pp. 7836-7849
Author(s):  
P Russo ◽  
W Z Li ◽  
Z Guo ◽  
F Sherman
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Site Directed Mutagenesis ◽  
Yeast Cells ◽  
In Vitro Mutagenesis ◽  
Yeast Saccharomyces Cerevisiae ◽  
Upstream Element ◽  
A Site ◽  
Derivatives Of ◽  
Acting In Concert

The cyc1-512 mutant was previously shown to contain a 38-bp deletion, 8 nucleotides upstream from the major wild-type poly(A) site, in the CYC1 gene, which encodes iso-1-cytochrome c of the yeast Saccharomyces cerevisiae. This 38-bp deletion caused a 90% reduction in the CYC1 transcripts, which were heterogeneous in size, aberrantly long, and presumably labile (K. S. Zaret and F. Sherman, Cell 28:563-573, 1982). Site-directed mutagenesis in and adjacent to the 38-bp region was used to identify signals involved in the formation and positioning of CYC1 mRNA 3' ends. In addition, combinations of various putative 3' end-forming signals were introduced by in vitro mutagenesis into the 3' region of the cyc1-512 mutant. The combined results from both studies suggest that 3' end formation in yeast cells involves signals having the following three distinct but integrated elements acting in concert: (i) the upstream element, including sequences TATATA, TAG ... TATGTA, and TTTTTATA, which function by enhancing the efficiency of downstream elements; (ii) downstream elements, such as TTAAGAAC and AAGAA, which position the poly(A) site; and (iii) the actual site of polyadenylation, which often occurs after cytidine residues that are 3' to the so-called downstream element. While the upstream element is required for efficient 3' end formation, alterations of the downstream element and poly(A) sites generally do not affect the efficiency of 3' end formation but appear to alter the positions of poly(A) sites. In addition, we have better defined the upstream elements by examining various derivatives of TATATA and TAG ... TATGTA, and we have examined the spatial requirements of the three elements by systematically introducing or deleting upstream and downstream elements and cytidine poly(A) sites.

scholarly journals The Neuroprotective Effects of Astaxanthin: Therapeutic Targets and Clinical Perspective

Molecules ◽  
2019 ◽  
Vol 24 (14) ◽  
pp. 2640 ◽  
Author(s):  
Fakhri ◽  
Aneva ◽  
Farzaei ◽  
Sobarzo-Sánchez
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Disorders ◽  
Neurological Disorders ◽  
Spinal Cord Injuries ◽  
Neurological Diseases ◽  
Mechanisms Of Action ◽  
Clinical Perspective ◽  
Neuroprotective Effects ◽  
Brain And Spinal Cord ◽  
Neuronal Disorders

As the leading causes of human disability and mortality, neurological diseases affect millions of people worldwide and are on the rise. Although the general roles of several signaling pathways in the pathogenesis of neurodegenerative disorders have so far been identified, the exact pathophysiology of neuronal disorders and their effective treatments have not yet been precisely elucidated. This requires multi-target treatments, which should simultaneously attenuate neuronal inflammation, oxidative stress, and apoptosis. In this regard, astaxanthin (AST) has gained growing interest as a multi-target pharmacological agent against neurological disorders including Parkinson’s disease (PD), Alzheimer’s disease (AD), brain and spinal cord injuries, neuropathic pain (NP), aging, depression, and autism. The present review highlights the neuroprotective effects of AST mainly based on its anti-inflammatory, antioxidative, and anti-apoptotic properties that underlies its pharmacological mechanisms of action to tackle neurodegeneration. The need to develop novel AST delivery systems, including nanoformulations, targeted therapy, and beyond, is also considered.

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