scholarly journals α-Synuclein conformational strains spread, seed and target neuronal cells differentially after injection into the olfactory bulb

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Nolwen L. Rey ◽  
Luc Bousset ◽  
Sonia George ◽  
Zachary Madaj ◽  
Lindsay Meyerdirk ◽  
...  
Keyword(s):  
Olfactory Bulb ◽  
De Novo ◽  
Structural Features ◽  
Alpha Synuclein ◽  
Ample Evidence ◽  
Neuronal Connections ◽  
Wild Type Female ◽  
Culture Models ◽  
The Brain

AbstractAlpha-synuclein inclusions, the hallmarks of synucleinopathies, are suggested to spread along neuronal connections in a stereotypical pattern in the brains of patients. Ample evidence now supports that pathological forms of alpha-synuclein propagate in cell culture models and in vivo in a prion-like manner. However, it is still not known why the same pathological protein targets different cell populations, propagates with different kinetics and leads to a variety of diseases (synucleinopathies) with distinct clinical features. The aggregation of the protein alpha-synuclein yields different conformational polymorphs called strains. These strains exhibit distinct biochemical, physical and structural features they are able to imprint to newly recruited alpha-synuclein. This had led to the view that the clinical heterogeneity observed in synucleinopathies might be due to distinct pathological alpha-synuclein strains.To investigate the pathological effects of alpha-synuclein strains in vivo, we injected five different pure strains we generated de novo (fibrils, ribbons, fibrils-65, fibrils-91, fibrils-110) into the olfactory bulb of wild-type female mice. We demonstrate that they seed and propagate pathology throughout the olfactory network within the brain to different extents. We show strain-dependent inclusions formation in neurites or cell bodies. We detect thioflavin S-positive inclusions indicating the presence of mature amyloid aggregates.In conclusion, alpha-synuclein strains seed the aggregation of their cellular counterparts to different extents and spread differentially within the central nervous system yielding distinct propagation patterns. We provide here the proof-of-concept that the conformation adopted by alpha-synuclein assemblies determines their ability to amplify and propagate in the brain in vivo. Our observations support the view that alpha-synuclein polymorphs may underlie different propagation patterns within human brains.

scholarly journals A Pachygyria-causing α-Tubulin Mutation Results in Inefficient Cycling with CCT and a Deficient Interaction with TBCB

2008 ◽  
Vol 19 (3) ◽  
pp. 1152-1161 ◽  
Author(s):  
Guoling Tian ◽  
Xiang-Peng Kong ◽  
Xavier H. Jaglin ◽  
Jamel Chelly ◽  
David Keays ◽  
...  
Keyword(s):  
De Novo Assembly ◽  
Structural Integrity ◽  
De Novo ◽  
Disease Phenotype ◽  
Tubulin Gene ◽  
Folding Intermediates ◽  
Diminished Capacity ◽  
The Brain ◽  
Dependent Interaction

The agyria (lissencephaly)/pachygyria phenotypes are catastrophic developmental diseases characterized by abnormal folds on the surface of the brain and disorganized cortical layering. In addition to mutations in at least four genes—LIS1, DCX, ARX and RELN—mutations in a human α-tubulin gene, TUBA1A, have recently been identified that cause these diseases. Here, we show that one such mutation, R264C, leads to a diminished capacity of de novo tubulin heterodimer formation. We identify the mechanisms that contribute to this defect. First, there is a reduced efficiency whereby quasinative α-tubulin folding intermediates are generated via ATP-dependent interaction with the cytosolic chaperonin CCT. Second, there is a failure of CCT-generated folding intermediates to stably interact with TBCB, one of the five tubulin chaperones (TBCA–E) that participate in the pathway leading to the de novo assembly of the tubulin heterodimer. We describe the behavior of the R264C mutation in terms of its effect on the structural integrity of α-tubulin and its interaction with TBCB. In spite of its compromised folding efficiency, R264C molecules that do productively assemble into heterodimers are capable of copolymerizing into dynamic microtubules in vivo. The diminished production of TUBA1A tubulin in R264C individuals is consistent with haploinsufficiency as a cause of the disease phenotype.

scholarly journals Conversion of ethanolamine, monomethylethanolamine and dimethylethanolamine to choline-containing compounds by neurons in culture and by the rat brain

1989 ◽  
Vol 264 (2) ◽  
pp. 555-562 ◽  
Author(s):  
C Andriamampandry ◽  
L Freysz ◽  
J N Kanfer ◽  
H Dreyfus ◽  
R Massarelli
Keyword(s):  
Rat Brain ◽  
Primary Culture ◽  
De Novo ◽  
Water Soluble ◽  
Intraventricular Injection ◽  
Chick Embryos ◽  
Fetal Rat ◽  
Derivatives Of ◽  
The Brain

The incubation of neurons from chick embryos in primary culture with [3H]ethanolamine revealed the conversion of this base into monomethyl, dimethyl and choline derivatives, including the corresponding free bases. Labelling with [methyl-3H]monomethylethanolamine and [methyl-3H]dimethylethanolamine supported the conclusion that in chick neuron cultures, phosphoethanolamine appears to be the preferential substrate for methylation, rather than ethanolamine or phosphatidylethanolamine. The methylation of the latter two compounds, in particular that of phosphatidylethanolamine, was seemingly stopped at the level of their monomethyl derivatives. Fetal rat neurons in primary culture incubated with [3H]ethanolamine showed similar results to those observed with chick neurones. However, phosphoethanolamine and phosphatidylethanolamine and, to a lesser extent, free ethanolamine, appeared to be possible substrates for methylation reactions. The methylation of water-soluble ethanolamine compounds de novo was further confirmed by experiments performed in vivo by intraventricular injection of [3H]ethanolamine. Phosphocholine and the monomethyl and dimethyl derivatives of ethanolamine were detected in the brain 15 min after injection.

scholarly journals Pre-Implantation Alcohol Exposure Induces Lasting Sex-Specific DNA Methylation Programming Errors in the Developing Forebrain

2020 ◽  
Author(s):  
LM Legault ◽  
K Doiron ◽  
M Breton-Larrivée ◽  
A Langford-Avelar ◽  
A Lemieux ◽  
...  
Keyword(s):  
Dna Methylation ◽  
De Novo ◽  
Prenatal Alcohol Exposure ◽  
Alcohol Exposure ◽  
Fetal Alcohol ◽  
Developmental Program ◽  
Genome Wide ◽  
Fetal Alcohol Spectrum ◽  
The Brain

ABSTRACTPrenatal alcohol exposure is recognized for altering DNA methylation profiles of brain cells during development, and to be part of the molecular basis underpinning Fetal Alcohol Spectrum Disorder (FASD) etiology. However, we have negligible information on the effects of alcohol exposure during pre-implantation, the early embryonic window marked with dynamic DNA methylation reprogramming, and on how this may rewire the brain developmental program. Using a pre-clinical in vivo mouse model, we show that pre-implantation alcohol exposure leads to adverse developmental outcomes that replicate clinical characteristics observed in children with FASD. Genome-wide DNA methylation analyses of fetal forebrains uncovered sex-specific alterations, including partial loss of DNA methylation maintenance at imprinting control regions, and abnormal de novo DNA methylation profiles in various biological pathways (e.g., neural/brain development). These findings support the contribution of alcohol-induced DNA methylation programming deviations during pre-implantation to the manifestation of neurodevelopmental phenotypes associated with FASD.

Visual function in regenerating teleost retina following cytotoxic lesioning

1999 ◽  
Vol 16 (2) ◽  
pp. 241-251 ◽  
Author(s):  
ALLEN F. MENSINGER ◽  
MAUREEN K. POWERS
Keyword(s):  
Visual Function ◽  
Postural Balance ◽  
Wave Amplitude ◽  
Synaptic Connections ◽  
Visual Behavior ◽  
Intraocular Injection ◽  
Neuronal Connections ◽  
Teleost Retina ◽  
The Brain

Teleost fish retinas can regenerate in vivo in adulthood. Retinal and visual function was assessed in adult goldfish following comprehensive retinal destruction by intraocular injection of ouabain. Electroretinograms (ERGs) and the dorsal light reflex (DLR) were used to evaluate the return of visual function. ERGs were detectable in regenerating eyes 50 to 70 days following ouabain injection. Amplitudes of both a- and b-waves increased steadily through day 210 following ouabain treatment, at which time a-wave amplitude was 90% and b-wave amplitude approached 50% of the contralateral control eye. The progressive gain observed in the a-wave was attributed to photoreceptor regeneration. The increase in b-wave amplitude was attributed to an increase in the number of inner nuclear layer cells and the number and efficacy of neuronal connections to or within the inner retina. The photopic spectral sensitivity of the b-wave in regenerating retina closely matched the intrafish control retina, suggesting that the relative numbers of cone photoreceptors was normal in regeneration. The recovery of the DLR (indicated by improved postural balance during regeneration) paralleled electrophysiological gains during retinal regeneration. Fish displayed a marked longitudinal body imbalance toward the control eye following retinal destruction. Improvement in equilibrium was correlated with increasing b-wave amplitudes. When the b-wave reached 50% of control amplitude (30 weeks), normal posture was restored. The return of the ERG indicates that photoreceptors and their synaptic connections must be functional in regenerating retina. Failure of the retina to regenerate produced an abnormal DLR that persisted through 30 weeks and ERGs were not measurable. The return of normal equilibrium indicates that the regenerating retina can establish central connections to the brain, and that the regenerated connections can mediate functional visual behavior.

scholarly journals α-Synuclein strains influence multiple system atrophy via central and peripheral mechanisms

2020 ◽  
Author(s):  
T. Torre Murazabal ◽  
A. Van der Perren ◽  
A. Coens ◽  
A. Barber Janer ◽  
S. Camacho-Garcia ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Disease Progression ◽  
Structural Features ◽  
Protein Deposits ◽  
Disease Subtypes ◽  
Different Strains ◽  
Peripheral Immune Cells ◽  
The Brain

AbstractMultiple system atrophy (MSA) is a progressive neurodegenerative disease with prominent autonomic and motor features. Different disease subtypes are distinguished by their predominant parkinsonian or cerebellar signs. The pathognomonic feature of MSA is the presence of α-synuclein (αSyn) protein deposits in glial cells of the central and peripheral nervous system. It is unclear why MSA, that invariably presents with αSyn pathology, is clinically so heterogeneous, why it progresses at varying rates and how neuroinflammation affects disease progression. Recently, it was shown that different strains of αSyn can assemble in unique disease environments but also that a variety of strains might exist in the brain of MSA patients. We therefore investigated if different αSyn strains might influence MSA disease progression. To this aim, we injected two recombinant strains of αSyn in MSA transgenic mice and found that they significantly impact MSA disease progression in a strain-dependent way via oligodendroglial, neurotoxic and immune-related mechanisms. Neurodegeneration and brain atrophy were accompanied by unique microglial and astroglial responses and the recruitment of central and peripheral immune cells. The differential activation of microglial cells correlated with the structural features of αSyn strains both in vitro and in vivo. By injecting αSyn strains in MSA mice we could more closely mimic a comprehensive MSA phenotype in an experimental setting. This study therefore shows that i) MSA phenotype is governed by both the αSyn strain nature and the host environment and ii) αSyn strains can directly trigger a detrimental immune response related to disease progression in MSA.

scholarly journals TriPepSVM - de novo prediction of RNA-binding proteins based on short amino acid motifs

2018 ◽  
Author(s):  
Annkatrin Bressin ◽  
Roman Schulte-Sasse ◽  
Davide Figini ◽  
Erika C Urdaneta ◽  
Benedikt M Beckmann ◽  
...  
Keyword(s):  
Binding Proteins ◽  
Rna Binding ◽  
De Novo ◽  
Rna Binding Proteins ◽  
Low Complexity ◽  
Structural Features ◽  
Support Vector ◽  
String Kernels ◽  
Rna Binders

In recent years hundreds of novel RNA-binding proteins (RBPs) have been identified leading to the discovery of novel RNA-binding domains (RBDs). Furthermore, unstructured or disordered low-complexity regions of RBPs have been identified to play an important role in interactions with nucleic acids. However, these advances in understanding RBPs are limited mainly to eukaryotic species and we only have limited tools to faithfully predict RNA-binders from bacteria. Here, we describe a support vector machine (SVM)-based method, called TriPepSVM, for the classification of RNA-binding proteins and non-RBPs. TriPepSVM applies string kernels to directly handle protein sequences using tri-peptide frequencies. Testing the method in human and bacteria, we find that several RBP-enriched tripeptides occur more often in structurally disordered regions of RBPs. TriPepSVM outperforms existing applications, which consider classical structural features of RNA-binding or homology, in the task of RBP prediction in both human and bacteria. Finally, we predict 66 novel RBPs in Salmonella Typhimurium and validate the bacterial proteins ClpX, DnaJ and UbiG to associate with RNA in vivo.

scholarly journals Locus coeruleus imaging as a biomarker for noradrenergic dysfunction in neurodegenerative diseases

Brain ◽  
2019 ◽  
Vol 142 (9) ◽  
pp. 2558-2571 ◽  
Author(s):  
Matthew J Betts ◽  
Evgeniya Kirilina ◽  
Maria C G Otaduy ◽  
Dimo Ivanov ◽  
Julio Acosta-Cabronero ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Locus Coeruleus ◽  
Disease Progression ◽  
Structural Features ◽  
Behavioural Symptoms ◽  
Non Invasive ◽  
Neurodegenerative Dementias ◽  
The Brain ◽  
In Vivo Assessment

Abstract Pathological alterations to the locus coeruleus, the major source of noradrenaline in the brain, are histologically evident in early stages of neurodegenerative diseases. Novel MRI approaches now provide an opportunity to quantify structural features of the locus coeruleus in vivo during disease progression. In combination with neuropathological biomarkers, in vivo locus coeruleus imaging could help to understand the contribution of locus coeruleus neurodegeneration to clinical and pathological manifestations in Alzheimer’s disease, atypical neurodegenerative dementias and Parkinson’s disease. Moreover, as the functional sensitivity of the noradrenergic system is likely to change with disease progression, in vivo measures of locus coeruleus integrity could provide new pathophysiological insights into cognitive and behavioural symptoms. Locus coeruleus imaging also holds the promise to stratify patients into clinical trials according to noradrenergic dysfunction. In this article, we present a consensus on how non-invasive in vivo assessment of locus coeruleus integrity can be used for clinical research in neurodegenerative diseases. We outline the next steps for in vivo, post-mortem and clinical studies that can lay the groundwork to evaluate the potential of locus coeruleus imaging as a biomarker for neurodegenerative diseases.

scholarly journals Tau and Alpha Synuclein Synergistic Effect in Neurodegenerative Diseases: When the Periphery Is the Core

2020 ◽  
Vol 21 (14) ◽  
pp. 5030
Author(s):  
Elena Vacchi ◽  
Alain Kaelin-Lang ◽  
Giorgia Melli
Keyword(s):  
Neurodegenerative Diseases ◽  
Alpha Synuclein ◽  
Anatomical Connectivity ◽  
Peripheral Tissues ◽  
Parkinson’S Diseases ◽  
Relevant Role ◽  
The Brain ◽  
Dying Back

In neuronal cells, tau is a microtubule-associated protein placed in axons and alpha synuclein is enriched at presynaptic terminals. They display a propensity to form pathologic aggregates, which are considered the underlying cause of Alzheimer’s and Parkinson’s diseases. Their functional impairment induces loss of axonal transport, synaptic and mitochondrial disarray, leading to a “dying back” pattern of degeneration, which starts at the periphery of cells. In addition, pathologic spreading of alpha-synuclein from the peripheral nervous system to the brain through anatomical connectivity has been demonstrated for Parkinson’s disease. Thus, examination of the extent and types of tau and alpha-synuclein in peripheral tissues and their relation to brain neurodegenerative diseases is of relevance since it may provide insights into patterns of protein aggregation and neurodegeneration. Moreover, peripheral nervous tissues are easily accessible in-vivo and can play a relevant role in the early diagnosis of these conditions. Up-to-date investigations of tau species in peripheral tissues are scant and have mainly been restricted to rodents, whereas, more evidence is available on alpha synuclein in peripheral tissues. Here we aim to review the literature on the functional role of tau and alpha synuclein in physiological conditions and disease at the axonal level, their distribution in peripheral tissues, and discuss possible commonalities/diversities as well as their interaction in proteinopathies.

Thermally reduced graphene is a permissive material for neurons and astrocytes and de novo neurogenesis in the adult olfactory bulb in vivo

Biomaterials ◽  
2016 ◽  
Vol 82 ◽  
pp. 84-93 ◽  
Author(s):  
Çağla Defteralı ◽  
Raquel Verdejo ◽  
Laura Peponi ◽  
Eduardo D. Martín ◽  
Ricardo Martínez-Murillo ◽  
...  
Keyword(s):  
Olfactory Bulb ◽  
De Novo ◽  
Reduced Graphene

scholarly journals Brain structural complexity and consciousness

2021 ◽  
Vol 2 ◽  
Author(s):  
Chen Song
Keyword(s):  
Brain Imaging ◽  
Brain Volume ◽  
Imaging Techniques ◽  
Physical Space ◽  
Structural Diversity ◽  
Brain Regions ◽  
Metabolic Energy ◽  
Neuronal Connections ◽  
The Brain

Structure shapes function. Understanding what is structurally special about the brain that allows it to generate consciousness remains a fundamental scientific challenge. Recently, advances in brain imaging techniques have made it possible to measure the structure of human brain, from the morphology of neurons and neuronal connections to the gross anatomy of brain regions, in-vivo and non-invasively. Using advanced brain imaging techniques, it was discovered that the structural diversity between neurons and the topology of neuronal connections, as opposed to the sheer number of neurons or neuronal connections, are key to consciousness. When the structural diversity is high and the connections follow a modular topology, neurons will become functionally differentiable and functionally integrable with one another. The high levels of differentiation and integration, in turn, enable the brain to produce the richest conscious experiences from the smallest number of neurons and neuronal connections. Consequently, across individuals, those with a smaller brain volume but a higher structural diversity tend to have richer conscious experiences than those with a larger brain volume but a lower structural diversity. Moreover, within individuals, a reduction in neuronal connections, if accompanied by an increase in structural diversity, will result in richer conscious experiences, and vice versa. These findings suggest that having a larger number of neurons and neuronal connections is not necessarily beneficial for consciousness; in contrast, an optimal brain architecture for consciousness is one where the richest conscious experiences are generated from the smallest number of neurons and neuronal connections, at the minimal cost of biological material, physical space, and metabolic energy.

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