scholarly journals Proteomic Analysis of Hydromethylthionine in the Line 66 Model of Frontotemporal Dementia Demonstrates Actions on Tau-Dependent and Tau-Independent Networks

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2162
Author(s):  
Karima Schwab ◽  
Valeria Melis ◽  
Charles R. Harrington ◽  
Claude M. Wischik ◽  
Mandy Magbagbeolu ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Stress Responses ◽  
Protein Ubiquitination ◽  
Brain Proteome ◽  
Homeostatic Function ◽  
Behavioural Phenotypes ◽  
Tau Aggregation ◽  
The Brain ◽  
Key Pathways ◽  
Dimensional Electrophoresis

Abnormal aggregation of tau is the pathological hallmark of tauopathies including frontotemporal dementia (FTD). We have generated tau-transgenic mice that express the aggregation-prone P301S human tau (line 66). These mice present with early-onset, high tau load in brain and FTD-like behavioural deficiencies. Several of these behavioural phenotypes and tau pathology are reversed by treatment with hydromethylthionine but key pathways underlying these corrections remain elusive. In two proteomic experiments, line 66 mice were compared with wild-type mice and then vehicle and hydromethylthionine treatments of line 66 mice were compared. The brain proteome was investigated using two-dimensional electrophoresis and mass spectrometry to identify protein networks and pathways that were altered due to tau overexpression or modified by hydromethylthionine treatment. Overexpression of mutant tau induced metabolic/mitochondrial dysfunction, changes in synaptic transmission and in stress responses, and these functions were recovered by hydromethylthionine. Other pathways, such as NRF2, oxidative phosphorylation and protein ubiquitination were activated by hydromethylthionine, presumably independent of its function as a tau aggregation inhibitor. Our results suggest that hydromethylthionine recovers cellular activity in both a tau-dependent and a tau-independent fashion that could lead to a wide-spread improvement of homeostatic function in the FTD brain.

scholarly journals Network analysis of the brain proteome of GRN knockout mice reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations

2020 ◽  
Vol 16 (S3) ◽  
Author(s):  
Thomas Kukar ◽  
Meixiang Huang ◽  
Erica S Modeste ◽  
Eric B Dammer ◽  
Christopher J Holler ◽  
...  
Keyword(s):  
Network Analysis ◽  
Frontotemporal Dementia ◽  
Knockout Mice ◽  
Pathogenic Mechanisms ◽  
Brain Proteome ◽  
The Brain

The Limits of Emotion

2018 ◽  
Author(s):  
Joshua May
Keyword(s):  
Moral Judgment ◽  
Frontotemporal Dementia ◽  
Empirical Research ◽  
Emotional Processing ◽  
Moral Cognition ◽  
Moral Norms ◽  
Moral Concepts ◽  
Integral Role ◽  
The Brain

Empirical research apparently suggests that emotions play an integral role in moral judgment. The evidence for sentimentalism is diverse, but it is rather weak and has generally been overblown. There is no evidence that our moral concepts themselves are partly composed of or necessarily dependent on emotions. While the moral/conventional distinction may partly characterize the essence of moral judgment, moral norms needn’t be backed by affect in order to transcend convention. Priming people with incidental emotions like disgust doesn’t make them moralize actions. Finally, moral judgment can only be somewhat impaired by damage to areas of the brain that are generally associated with emotional processing (as in acquired sociopathy and frontotemporal dementia). While psychopaths exhibit both emotional and rational deficits, the latter alone can explain any minor defects in moral cognition.

scholarly journals Co-factor-free aggregation of tau into seeding-competent RNA-sequestering amyloid fibrils

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Pijush Chakraborty ◽  
Gwladys Rivière ◽  
Shu Liu ◽  
Alain Ibáñez de Opakua ◽  
Rıza Dervişoğlu ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Corticobasal Degeneration ◽  
Binding Studies ◽  
Rigid Core ◽  
Tau Aggregation ◽  
The Brain ◽  
Tau Aggregate ◽  
Disease Specific ◽  
Tau Fibrils

AbstractPathological aggregation of the protein tau into insoluble aggregates is a hallmark of neurodegenerative diseases. The emergence of disease-specific tau aggregate structures termed tau strains, however, remains elusive. Here we show that full-length tau protein can be aggregated in the absence of co-factors into seeding-competent amyloid fibrils that sequester RNA. Using a combination of solid-state NMR spectroscopy and biochemical experiments we demonstrate that the co-factor-free amyloid fibrils of tau have a rigid core that is similar in size and location to the rigid core of tau fibrils purified from the brain of patients with corticobasal degeneration. In addition, we demonstrate that the N-terminal 30 residues of tau are immobilized during fibril formation, in agreement with the presence of an N-terminal epitope that is specifically detected by antibodies in pathological tau. Experiments in vitro and in biosensor cells further established that co-factor-free tau fibrils efficiently seed tau aggregation, while binding studies with different RNAs show that the co-factor-free tau fibrils strongly sequester RNA. Taken together the study provides a critical advance to reveal the molecular factors that guide aggregation towards disease-specific tau strains.

Deletion of murine tau gene increases tau aggregation in a human mutant tau transgenic mouse model

2010 ◽  
Vol 38 (4) ◽  
pp. 1001-1005 ◽  
Author(s):  
Kunie Ando ◽  
Karelle Leroy ◽  
Céline Heraud ◽  
Anna Kabova ◽  
Zehra Yilmaz ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transgenic Mouse ◽  
Double Mutant ◽  
Transgenic Mouse Model ◽  
Tau Proteins ◽  
Dependent Manner ◽  
Age Dependent ◽  
Ad Alzheimer’S Disease ◽  
Tau Aggregation ◽  
The Brain

We have reported previously a tau transgenic mouse model (Tg30tau) overexpressing human 4R1N double-mutant tau (P301S and G272V) and that develops AD (Alzheimer's disease)-like NFTs (neurofibrillary tangles) in an age-dependent manner. Since murine tau might interfere with the toxic effects of human mutant tau, we set out to analyse the phenotype of our Tg30tau model in the absence of endogenous murine tau with the aim to reproduce more faithfully a model of human tauopathy. By crossing the Tg30tau line with TauKO (tau-knockout) mice, we have obtained a new mouse line called Tg30×TauKO that expresses only exogenous human double-mutant 4R1N tau. Whereas Tg30×TauKO mice express fewer tau proteins compared with Tg30tau, they exhibit augmented sarkosyl-insoluble tau in the brain and an increased number of Gallyas-positive NFTs in the hippocampus. Taken together, exclusion of murine tau causes accelerated tau aggregation during aging of this mutant tau transgenic model.

scholarly journals Sporadic C reutzfeldt– J akob disease subtype‐specific alterations of the brain proteome: Impact on R ab3a recycling

PROTEOMICS ◽  
2012 ◽  
Vol 12 (23-24) ◽  
pp. 3610-3620 ◽  
Author(s):  
Joanna Gawinecka ◽  
Franco Cardone ◽  
Abdul R. Asif ◽  
Angela De Pascalis ◽  
Wiebke M. Wemheuer ◽  
...  
Keyword(s):  
Disease Subtype ◽  
Brain Proteome ◽  
The Brain

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.

How the Brain Moves the Eyes

2014 ◽  
pp. 1-25
Author(s):  
Shirley H. Wray
Keyword(s):  
Cardiac Surgery ◽  
Eye Movements ◽  
Progressive Supranuclear Palsy ◽  
Disease Progression ◽  
Frontotemporal Dementia ◽  
Smooth Pursuit ◽  
Cortical Areas ◽  
Initial Symptoms ◽  
The Brain ◽  
Symptoms And Signs

discusses the brain’s visual architecture for directing and controlling of eye movements:the striate, frontal and parietal cortical areas; and the eye movements themselves—saccades, smooth pursuit, and vergence. The susceptibility to disorders of these systems is illustrated in four detailed cases that follow disease progression from initial symptoms and signs to diagnosis and treatment. The case studies and video displays include a patient with Pick’s disease (frontotemporal dementia), another with Alzheimer’s dementia, and two examples of rare saccadic syndromes, one a patient with the slow saccade syndrome due to progressive supranuclear palsy and one with selective saccadic palsy following cardiac surgery.

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