scholarly journals Alpha-Synuclein: Mechanisms of Release and Pathology Progression in Synucleinopathies

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 375
Author(s):  
Inês C. Brás ◽  
Tiago F. Outeiro
Keyword(s):  
Molecular Mechanisms ◽  
Brain Regions ◽  
Alpha Synuclein ◽  
Therapeutic Strategies ◽  
Cell Protein ◽  
Protein Assemblies ◽  
Lewy Pathology ◽  
Tremendous Progress ◽  
The Brain ◽  
Made In

The accumulation of misfolded alpha-synuclein (aSyn) throughout the brain, as Lewy pathology, is a phenomenon central to Parkinson’s disease (PD) pathogenesis. The stereotypical distribution and evolution of the pathology during disease is often attributed to the cell-to-cell transmission of aSyn between interconnected brain regions. The spreading of conformationally distinct aSyn protein assemblies, commonly referred as strains, is thought to result in a variety of clinically and pathologically heterogenous diseases known as synucleinopathies. Although tremendous progress has been made in the field, the mechanisms involved in the transfer of these assemblies between interconnected neural networks and their role in driving PD progression are still unclear. Here, we present an update of the relevant discoveries supporting or challenging the prion-like spreading hypothesis. We also discuss the importance of aSyn strains in pathology progression and the various putative molecular mechanisms involved in cell-to-cell protein release. Understanding the pathways underlying aSyn propagation will contribute to determining the etiology of PD and related synucleinopathies but also assist in the development of new therapeutic strategies.

scholarly journals Molecular Mechanisms of Drug Resistance in Glioblastoma

2021 ◽  
Vol 22 (12) ◽  
pp. 6385
Author(s):  
Maya A. Dymova ◽  
Elena V. Kuligina ◽  
Vladimir A. Richter
Keyword(s):  
Drug Resistance ◽  
Brain Tumor ◽  
Molecular Mechanisms ◽  
Primary Brain Tumor ◽  
Therapeutic Resistance ◽  
Molecular Characteristics ◽  
Blood Brain ◽  
Conventional Radiation ◽  
The Brain ◽  
Made In

Glioblastoma multiforme (GBM) is the most common and fatal primary brain tumor, is highly resistant to conventional radiation and chemotherapy, and is not amenable to effective surgical resection. The present review summarizes recent advances in our understanding of the molecular mechanisms of therapeutic resistance of GBM to already known drugs, the molecular characteristics of glioblastoma cells, and the barriers in the brain that underlie drug resistance. We also discuss the progress that has been made in the development of new targeted drugs for glioblastoma, as well as advances in drug delivery across the blood–brain barrier (BBB) and blood–brain tumor barrier (BBTB).

scholarly journals Developmental cannabidiol exposure increases anxiety and modifies genome-wide brain DNA methylation in adult female mice

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Nicole M. Wanner ◽  
Mathia Colwell ◽  
Chelsea Drown ◽  
Christopher Faulk
Keyword(s):  
Dna Methylation ◽  
Molecular Mechanisms ◽  
Coat Color ◽  
Brain Regions ◽  
Functional Enrichment ◽  
Positive Effects ◽  
Genome Wide ◽  
Nulliparous Female ◽  
The Impact ◽  
The Brain

Abstract Background Use of cannabidiol (CBD), the primary non-psychoactive compound found in cannabis, has recently risen dramatically, while relatively little is known about the underlying molecular mechanisms of its effects. Previous work indicates that direct CBD exposure strongly impacts the brain, with anxiolytic, antidepressant, antipsychotic, and other effects being observed in animal and human studies. The epigenome, particularly DNA methylation, is responsive to environmental input and can direct persistent patterns of gene regulation impacting phenotype. Epigenetic perturbation is particularly impactful during embryogenesis, when exogenous exposures can disrupt critical resetting of epigenetic marks and impart phenotypic effects lasting into adulthood. The impact of prenatal CBD exposure has not been evaluated; however, studies using the psychomimetic cannabinoid Δ9-tetrahydrocannabinol (THC) have identified detrimental effects on psychological outcomes in developmentally exposed adult offspring. We hypothesized that developmental CBD exposure would have similar negative effects on behavior mediated in part by the epigenome. Nulliparous female wild-type Agouti viable yellow (Avy) mice were exposed to 20 mg/kg CBD or vehicle daily from two weeks prior to mating through gestation and lactation. Coat color shifts, a readout of DNA methylation at the Agouti locus in this strain, were measured in F1 Avy/a offspring. Young adult F1 a/a offspring were then subjected to tests of working spatial memory and anxiety/compulsive behavior. Reduced-representation bisulfite sequencing was performed on both F0 and F1 cerebral cortex and F1 hippocampus to identify genome-wide changes in DNA methylation for direct and developmental exposure, respectively. Results F1 offspring exposed to CBD during development exhibited increased anxiety and improved memory behavior in a sex-specific manner. Further, while no significant coat color shift was observed in Avy/a offspring, thousands of differentially methylated loci (DMLs) were identified in both brain regions with functional enrichment for neurogenesis, substance use phenotypes, and other psychologically relevant terms. Conclusions These findings demonstrate for the first time that despite positive effects of direct exposure, developmental CBD is associated with mixed behavioral outcomes and perturbation of the brain epigenome.

Insights into the molecular basis of host behaviour manipulation by Toxoplasma gondii infection

2017 ◽  
Vol 1 (6) ◽  
pp. 563-572 ◽  
Author(s):  
Pierre-Mehdi Hammoudi ◽  
Dominique Soldati-Favre
Keyword(s):  
Toxoplasma Gondii ◽  
Stress Responses ◽  
Molecular Mechanisms ◽  
Brain Regions ◽  
Intermediate Hosts ◽  
Toxoplasma Gondii Infection ◽  
Host Parasite ◽  
Host Behaviour ◽  
The Brain ◽  
Brain Homeostasis

Typically illustrating the ‘manipulation hypothesis’, Toxoplasma gondii is widely known to trigger sustainable behavioural changes during chronic infection of intermediate hosts to enhance transmission to its feline definitive hosts, ensuring survival and dissemination. During the chronic stage of infection in rodents, a variety of neurological dysfunctions have been unravelled and correlated with the loss of cat fear, among other phenotypic impacts. However, the underlying neurological alteration(s) driving these behavioural modifications is only partially understood, which makes it difficult to draw more than a correlation between T. gondii infection and changes in brain homeostasis. Moreover, it is barely known which among the brain regions governing fear and stress responses are preferentially affected during T. gondii infection. Studies aiming at an in-depth dissection of underlying molecular mechanisms occurring at the host and parasite levels will be discussed in this review. Addressing this reminiscent topic in the light of recent technical progress and new discoveries regarding fear response, olfaction and neuromodulator mechanisms could contribute to a better understanding of this complex host–parasite interaction.

scholarly journals Senescence in the aging process

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 1219 ◽  
Author(s):  
Richard GA Faragher ◽  
Anne McArdle ◽  
Alison Willows ◽  
Elizabeth L. Ostler
Keyword(s):  
Aging Process ◽  
Molecular Mechanisms ◽  
Senescent Cell ◽  
Cell Phenotype ◽  
Direct Demonstration ◽  
Tremendous Progress ◽  
Made In

The accumulation of ‘senescent’ cells has long been proposed to act as an ageing mechanism. These cells display a radically altered transcriptome and degenerative phenotype compared with their growing counterparts. Tremendous progress has been made in recent years both in understanding the molecular mechanisms controlling entry into the senescent state and in the direct demonstration that senescent cells act as causal agents of mammalian ageing. The challenges now are to gain a better understanding of how the senescent cell phenotype varies between different individuals and tissues, discover how senescence predisposes to organismal frailty, and develop mechanisms by which the deleterious effects of senescent cells can be ameliorated.

scholarly journals Transcriptomic analysis of frontotemporal lobar degeneration with TDP-43 pathology reveals cellular alterations across multiple brain regions

2021 ◽  
Author(s):  
Rahat Hasan ◽  
Jack Humphrey ◽  
Conceicao Bettencourt ◽  
Tammaryn Lashley ◽  
Pietro Fratta ◽  
...  
Keyword(s):  
Gene Expression ◽  
Frontotemporal Lobar Degeneration ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Temporal Cortex ◽  
Neuronal Loss ◽  
Underlying Disease ◽  
Brain Regions ◽  
Neuronal Markers ◽  
The Brain

Frontotemporal lobar degeneration (FTLD) is a group of heterogeneous neurodegenerative disorders affecting the frontal and temporal lobes of the brain. Nuclear loss and cytoplasmic aggregation of the RNA-binding protein TDP-43 represents the major FTLD pathology, known as FTLD-TDP. To date, there is no effective treatment for FTLD-TDP due to an incomplete understanding of the molecular mechanisms underlying disease development. Here we compared post-mortem tissue RNA-seq transcriptomes from the frontal cortex, temporal cortex and cerebellum between 28 controls and 30 FTLD-TDP patients to profile changes in cell-type composition, gene expression and transcript usage. We observed downregulation of neuronal markers in all three regions of the brain, accompanied by upregulation of microglia, astrocytes, and oligodendrocytes, as well as endothelial cells and pericytes, suggesting shifts in both immune activation and within the vasculature. We validate our estimates of neuronal loss using neuropathological atrophy scores and show that neuronal loss in the cortex can be mainly attributed to excitatory neurons, and that increases in microglial and endothelial cell expression are highly correlated with neuronal loss. All our analyses identified a strong involvement of the cerebellum in the neurodegenerative process of FTLD-TDP. Altogether, our data provides a detailed landscape of gene expression alterations to help unravel relevant disease mechanisms in FTLD.

scholarly journals Rhombencephalitis Caused byListeria monocytogenesin Humans and Ruminants: A Zoonosis on the Rise?

2010 ◽  
Vol 2010 ◽  
pp. 1-22 ◽  
Author(s):  
Anna Oevermann ◽  
Andreas Zurbriggen ◽  
Marc Vandevelde
Keyword(s):  
Listeria Monocytogenes ◽  
High Mortality ◽  
Host Species ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Therapeutic Strategies ◽  
Zoonotic Infection ◽  
Cns Disease ◽  
The Brain

Listeriosis is an emerging zoonotic infection of humans and ruminants worldwide caused byListeria monocytogenes(LM). In both host species, CNS disease accounts for the high mortality associated with listeriosis and includes rhombencephalitis, whose neuropathology is strikingly similar in humans and ruminants. This review discusses the current knowledge about listeric encephalitis, and involved host and bacterial factors. There is an urgent need to study the molecular mechanisms of neuropathogenesis, which are poorly understood. Such studies will provide a basis for the development of new therapeutic strategies that aim to prevent LM from invading the brain and spread within the CNS.

Genetic basis of Parkinson disease

2010 ◽  
Vol 28 (1) ◽  
pp. E7 ◽  
Author(s):  
Georgia Xiromerisiou ◽  
Efthimios Dardiotis ◽  
Vaïa Tsimourtou ◽  
Persa Maria Kountra ◽  
Konstantinos N. Paterakis ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Molecular Mechanisms ◽  
Autosomal Recessive Inheritance ◽  
Alpha Synuclein ◽  
Collaborative Studies ◽  
Common Genetic Variants ◽  
Cellular Pathways ◽  
Meta Analyses ◽  
Shed Light ◽  
Made In

Over the past few years, considerable progress has been made in understanding the molecular mechanisms of Parkinson disease (PD). Mutations in certain genes are found to cause monogenic forms of the disorder, with autosomal dominant or autosomal recessive inheritance. These genes include alpha-synuclein, parkin, PINK1, DJ-1, LRRK2, and ATP13A2. The monogenic variants are important tools in identifying cellular pathways that shed light on the pathogenesis of this disease. Certain common genetic variants are also likely to modulate the risk of PD. International collaborative studies and meta-analyses have identified common variants as genetic susceptibility risk/protective factors for sporadic PD.

scholarly journals Regional Brain Blood Flow, Blood Volume, and Haematocrit Values in the Adult Rat

1983 ◽  
Vol 3 (2) ◽  
pp. 254-256 ◽  
Author(s):  
Jill E. Cremer ◽  
Malcolm P. Seville
Keyword(s):  
Blood Flow ◽  
Blood Volume ◽  
Brain Regions ◽  
Adult Rats ◽  
Adult Rat ◽  
Systemic Artery ◽  
Significant Difference ◽  
Total Body ◽  
The Brain ◽  
Made In

Measurements of red cell volume, plasma volume, and tissue haematocrit (Hct) were made in 14 brain regions in adult rats using 51Cr-tagged red cells and 125I-labeled human serum albumin. The mean large vessel (systemic artery) Hct was 41.8, total body Hct was 35.3, and of the brain regions, the lowest value (septal nucleus) was 25.91 and the highest (visual cortex) was 32.05. The lowest blood volume was 6.29 μl g−1 (caudate putamen) and the highest was 14.44 μl g−1 (inferior colliculus). There was a significant difference between regions in both blood volume and tissue blood Hct. When brain regions were ranked in order of blood volume, this did not coincide with the order for blood flow.

scholarly journals Molecular Biology of Rotavirus Entry and Replication

2009 ◽  
Vol 9 ◽  
pp. 1476-1497 ◽  
Author(s):  
Marie Christine Ruiz ◽  
Theresa Leon ◽  
Yuleima Diaz ◽  
Fabian Michelangeli
Keyword(s):  
Molecular Mechanisms ◽  
Rna Virus ◽  
Viral Proteins ◽  
Therapeutic Strategies ◽  
Viral Gastroenteritis ◽  
Structural Studies ◽  
Double Stranded Rna ◽  
The Individual ◽  
Remarkable Progress ◽  
Made In

Rotavirus is a nonenveloped, double-stranded, RNA virus belonging to the Reoviridae family and is the major etiological agent of viral gastroenteritis in young children and young animals. Remarkable progress in the understanding of the rotavirus cycle has been made in the last 10 years. The knowledge of viral replication thus far acquired is based on structural studies, the expression and coexpression of individual viral proteins, silencing of individual genes by siRNAs, and the effects that these manipulations have on the physiology of the infected cell. The functions of the individual rotavirus proteins have been largely dissected; however, the interactions between them and with cell proteins, and the molecular mechanisms of virus replication, are just beginning to be understood. These advancements represent the basis for the development of effective vaccination and rational therapeutic strategies to combat rotavirus infection and diarrhea syndromes. In this paper, we review and try to integrate the new knowledge about rotavirus entry, replication, and assembly, and pose some of the questions that remain to be solved.

scholarly journals Mutant huntingtin reduces vesicular zinc level by inhibiting the binding of Sp1 to ZnT3 promoter

2020 ◽  
Author(s):  
Li Niu ◽  
Shiming Yang ◽  
Weixi Wang ◽  
Cui-fang Ye ◽  
He Li
Keyword(s):  
Molecular Mechanisms ◽  
Early Stage ◽  
Brain Regions ◽  
Zinc Level ◽  
Significant Loss ◽  
Zinc Homeostasis ◽  
Synaptic Dysfunction ◽  
Mutant Huntingtin ◽  
Bhk Cells ◽  
The Brain

Abstract Background Synaptic dysfunction caused by mutant huntingtin greatly contributes to Huntington’s disease (HD) pathogenesis. HD patients show cognitive impairment as well as uncontrolled movements. Vesicular zinc is closely linked to modulating synaptic transmission and maintaining cognitive ability. However, whether does mutant huntingtin affect zinc homeostasis in the brain or not? This will be of great significance for further revealing the pathogenesis of HD. Methods N171-HD82Q transgenic mice and cultured BHK cells expressing N-terminal mutant huntingtin fragment containing 160 glutamines (160Q BHK cells) were used to investigate the effect of mutant huntingtin on zinc homeostasis and its molecular mechanisms. Results Herein, we have demonstrated that the density of synaptic vesicular zinc decreases in the cortex, striatum and hippocampus of N171-82Q mice. Given that vesicular zinc concentration depends on the abundance of zinc transporter 3 (ZnT3) on the membrane of synaptic vesicles, ZnT3 expression is detected in the brain of N171-82Q mice and 160Q BHK cells. Mutant huntingtin leads to a dramatical decrease in ZnT3 mRNA and protein levels in the three brain regions of these mice aged from 14 to 20 weeks. Significantly, Sp1 activates ZnT3 transcription via its binding to the GC boxes in ZnT3 promoter. Nevertheless, mutant huntingtin inhibits the binding of Sp1 to the promoter of ZnT3 gene and down-regulates ZnT3 expression. Furthermore, the overexpression of Sp1 ameliorates inhibition of ZnT3 gene transcription by mutant huntingtin. Conclusions Collectively, this first study to reveal a significant loss of synaptic vesicular zinc and ZnT3 expression caused by mutant huntingtin in the early stage of HD. Our findings have revealed the molecular mechanism underlying this change. Mutant huntingtin inhibits the binding of Sp1 to ZnT3 gene promoter to reduce ZnT3 expression. The imbalance of vesicular zinc homeostasis may be closely associated with synaptic dysfunction and cognitive deficits in HD. This work sheds novel mechanistic insights into the pathogenesis of HD and promises a potential therapeutic strategy for HD.

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