Abstract Parkinson's disease and dementia with Lewy bodies are very frequent neurological disorders of the elderly. Mutations in the α-synuclein (αSYN) gene cause Parkinson's disease, often ...associated with dementia. Neuropathologically these diseases are characterized by the presence of Lewy bodies and Lewy neurites, intraneuronal inclusions mostly composed of αSYN protein fibrils. Moreover, αSYN is phosphorylated at S129 (phospho-serine-129 PSer129) in neuropathological lesions. Using our (Thy1)-A30PαSYN transgenic mouse model that develops age-dependent impairment in fear conditioning behavior, we investigated PSer129 immunostaining in the brain. We found distinct staining patterns using new, sensitive monoclonal antibodies. Somal and nuclear PSer129 immunoreactivity increased with age in hippocampal and cortical areas as well as the lateral/basolateral amygdalar nuclei and was present also in young, pre-symptomatic mice, but not wild-type controls. The tendency of PSer129 immunostaining to accumulate in the nucleus was confirmed in cell culture. (Thy1)–A30PαSYN transgenic mice further developed age-dependent, specific neuritic/terminal αSYN pathology in the medial parts of the central amygdalar nucleus and one of its projection areas, the lateral hypothalamus. Interestingly, this type of PSer129 neuropathology was thioflavine S negative, unlike the Lewy-like neuropathology present in the brain stem of (Thy1)-A30PαSYN mice. Thus, αSYN becomes phosphorylated in distinct parts of the brain in this α-synucleinopathy mouse model, showing age-dependent increases of nuclear PSer129 in cortical brain areas and the formation of neuritic/terminal PSer129 neuropathology with variable amyloid quality within the fear conditioning circuitry and the brain stem.
Long-Term Outcomes of ADHD Harpin, V.; Mazzone, L.; Raynaud, J. P. ...
Journal of attention disorders,
04/2016, Letnik:
20, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Objective: To compare the long-term self-esteem and social function outcomes of individuals with untreated and treated ADHD across childhood, adolescence, and adulthood. Method: A systematic search ...of 12 databases was performed to identify peer-reviewed, primary research articles, published January 1980 to December 2011, reporting long-term self-esteem and/or social function outcomes (≥2 years; life consequences distinct from symptoms) of individuals with untreated or treated ADHD. Results: Overall, 127 studies reported 150 outcomes. Most outcomes were poorer in individuals with untreated ADHD versus non-ADHD controls (57% 13/23 for self-esteem; 73% 52/71 for social function). A beneficial response to treatment (pharmacological, nonpharmacological, and multimodal treatments) was reported for the majority of self-esteem (89% 8/9) and social function (77% 17/22) outcomes. Conclusion: Untreated ADHD was associated with poorer long-term self-esteem and social function outcomes compared with non-ADHD controls. Treatment for ADHD was associated with improvement in outcomes; however, further long-term outcome studies are needed.
Context.
The Extreme Ultraviolet Imager (EUI) is part of the remote sensing instrument package of the ESA/NASA Solar Orbiter mission that will explore the inner heliosphere and observe the Sun from ...vantage points close to the Sun and out of the ecliptic. Solar Orbiter will advance the “connection science” between solar activity and the heliosphere.
Aims.
With EUI we aim to improve our understanding of the structure and dynamics of the solar atmosphere, globally as well as at high resolution, and from high solar latitude perspectives.
Methods.
The EUI consists of three telescopes, the Full Sun Imager and two High Resolution Imagers, which are optimised to image in Lyman-
α
and EUV (17.4 nm, 30.4 nm) to provide a coverage from chromosphere up to corona. The EUI is designed to cope with the strong constraints imposed by the Solar Orbiter mission characteristics. Limited telemetry availability is compensated by state-of-the-art image compression, onboard image processing, and event selection. The imposed power limitations and potentially harsh radiation environment necessitate the use of novel CMOS sensors. As the unobstructed field of view of the telescopes needs to protrude through the spacecraft’s heat shield, the apertures have been kept as small as possible, without compromising optical performance. This led to a systematic effort to optimise the throughput of every optical element and the reduction of noise levels in the sensor.
Results.
In this paper we review the design of the two elements of the EUI instrument: the Optical Bench System and the Common Electronic Box. Particular attention is also given to the onboard software, the intended operations, the ground software, and the foreseen data products.
Conclusions.
The EUI will bring unique science opportunities thanks to its specific design, its viewpoint, and to the planned synergies with the other Solar Orbiter instruments. In particular, we highlight science opportunities brought by the out-of-ecliptic vantage point of the solar poles, the high-resolution imaging of the high chromosphere and corona, and the connection to the outer corona as observed by coronagraphs.
While the initial pathology of Parkinson’s disease and other α‐synucleinopathies is often confined to circumscribed brain regions, it can spread and progressively affect adjacent and distant brain ...locales. This process may be controlled by cellular receptors of α‐synuclein fibrils, one of which was proposed to be the LAG3 immune checkpoint molecule. Here, we analysed the expression pattern of LAG3 in human and mouse brains. Using a variety of methods and model systems, we found no evidence for LAG3 expression by neurons. While we confirmed that LAG3 interacts with α‐synuclein fibrils, the specificity of this interaction appears limited. Moreover, overexpression of LAG3 in cultured human neural cells did not cause any worsening of α‐synuclein pathology ex vivo. The overall survival of A53T α‐synuclein transgenic mice was unaffected by LAG3 depletion, and the seeded induction of α‐synuclein lesions in hippocampal slice cultures was unaffected by LAG3 knockout. These data suggest that the proposed role of LAG3 in the spreading of α‐synucleinopathies is not universally valid.
SYNOPSIS
This study re‐evaluated the role of neuronal lymphocyte‐activation gene 3 (LAG3) in modulating the spreading of α‐synucleinopathies.
The expression of LAG3 in neurons could not be validated, using genomic and proteomic approaches.
The binding of α‐synuclein fibrils to LAG3 appeared to be limited regarding its specificity and affinity.
Overexpression of LAG3 in human neurons did not lead to an increased deposition of α‐synuclein aggregates ex vivo.
The genetic ablation of LAG3 did not lead to a prolonged survival of mice expressing human A53T α‐synuclein.
The absence of LAG3 did not influence the deposition of α‐synuclein inclusions in organotypic slice cultures.
This study re‐evaluated the role of neuronal lymphocyte‐activation gene 3 (LAG3) in modulating the spreading of α‐synucleinopathies.
•Parkinson’s disease (PD) may have an environmental component involving toxin exposure.•Trichloroethylene (TCE) is a major environmental contaminant and can convert to the toxin TaClo.•We ...administered TCE and TaClo to wild type and alpha-synuclein mutant mice as a model of PD.•TCE and TaClo caused substantia nigra neurone loss but alpha-synuclein mutation was not additive.
Parkinson’s disease (PD) is characterised pathologically by degeneration of the dopaminergic (DA) neurones of the substantia nigra pars compacta (SNpc) and the presence of α-synuclein containing Lewy body inclusions. Trichloroethylene (TCE) has been suggested as a potential environmental chemical that may contribute to the development of PD, via conversion to the neurotoxin, 1-Trichloromethyl-1,2,3,4-tetrahydro-β-carboline (TaClo). We investigated the effect of an 8 week exposure to TCE or TaClo on wild type and, as an experimental model of PD, A30P mutant α-synuclein overexpressing mice using a combination of behaviour and pathology. TCE or TaClo exposure caused significant DA neuronal loss within the SNpc in both wild type and transgenic mice. Cell numbers were lower in A30P animals than wild type, however, no additive effect of TCE or TaClo exposure and A30P overexpression was found. TCE or TaClo did not appear to lead to acceleration of motor or cognitive deficits in either wild type or A30P mutant mice, potentially because of the modest reductions of DA neuronal number in the SNpc. Our results do however suggest that TCE exposure could be a possible factor in development of PD like changes following exposure.
Trans-activation response DNA-binding protein of 43 kDa (TDP-43) regulates RNA processing and forms neuropathological aggregates in patients with amyotrophic lateral sclerosis and frontotemporal ...lobar degeneration. Investigating TDP-43 post-translational modifications, we discovered that K84 acetylation reduced nuclear import whereas K136 acetylation impaired RNA binding and splicing capabilities of TDP-43. Such failure of RNA interaction triggered TDP-43 phase separation mediated by the C-terminal low complexity domain, leading to the formation of insoluble aggregates with pathologically phosphorylated and ubiquitinated TDP-43. Introduction of acetyl-lysine at the identified sites via amber suppression confirmed the results from site-directed mutagenesis. K84-acetylated TDP-43 showed cytoplasmic mislocalization, and the aggregation propensity of K136-acetylated TDP-43 was confirmed. We generated antibodies selective for TDP-43 acetylated at these lysines, and found that sirtuin-1 can potently deacetylate K136-acetylated TDP-43 and reduce its aggregation propensity. Thus, distinct lysine acetylations modulate nuclear import, RNA binding and phase separation of TDP-43, suggesting regulatory mechanisms for TDP-43 pathogenesis.
A number of neurodegenerative disorders, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, are characterized by the intracellular deposition of fibrillar ...aggregates that contain a high proportion of alpha-synuclein (alphaS). The interaction with the membrane-water interface strongly modulates folding and aggregation of the protein. The present study investigates the lipid binding and the coil-helix transition of alphaS, using titration calorimetry, differential scanning calorimetry, and circular dichroism spectroscopy. Titration of the protein with small unilamellar vesicles composed of zwitterionic phospholipids below the chain melting temperature of the lipids yielded exceptionally large exothermic heat values. The sigmoidal titration curves were evaluated in terms of a simple model that assumes saturable binding sites at the vesicle surface. The cumulative heat release and the ellipticity were linearly correlated as a result of simultaneous binding and helix folding. There was no heat release and folding of alphaS in the presence of large unilamellar vesicles, indicating that a small radius of curvature is necessary for the alphaS-membrane interaction. The heat release and the negative heat capacity of the protein-vesicle interaction could not be attributed to the coil-helix transition of the protein alone. We speculate that binding and helix folding of alphaS depends on the presence of defect structures in the membrane-water interface, which in turn results in lipid ordering in the highly curved vesicular membranes. This will be discussed with regard to a possible role of the protein for the stabilization of synaptic vesicle membranes.
Phospho-Ser129 α-synuclein is the modified form of α-synuclein that occurs most frequently within Parkinson's disease pathological inclusions. Here we demonstrate that the antidiabetic drug metformin ...significantly reduces levels of phospho-Ser129 α-synuclein and the ratio of phospho-Ser129 α-synuclein to total α-synuclein. This effect was documented in vitro in SH-SY5Y and HeLa cells as well as in primary cultures of hippocampal neurons. In vitro work also elucidated the mechanisms underlying metformin's action. Following metformin exposure, decreased phospho-Ser129 α-synuclein was not strictly dependent on induction of AMP-activated protein kinase, a primary target of the drug. On the other hand, metformin-induced phospho-Ser129 α-synuclein reduction was consistently associated with inhibition of mammalian target of rapamycin (mTOR) and activation of protein phosphatase 2A (PP2A). Evidence supporting a key role of mTOR/PP2A signaling included the finding that, similar to metformin, the canonical mTOR inhibitor rapamycin was capable of lowering the ratio of phospho-Ser129 α-synuclein to total α-synuclein. Furthermore, no decrease in phosphorylated α-synuclein occurred with either metformin or rapamycin when phosphatase activity was inhibited, supporting a direct relationship between mTOR inhibition, PP2A activation and protein dephosphorylation. A final set of experiments confirmed the effectiveness of metformin in vivo in wild-type C57BL/6 mice. Addition of the drug to food or drinking water lowered levels of phospho-Ser129 α-synuclein in the brain of treated animals. These data reveal a new mechanism leading to α-synuclein dephosphorylation that could be targeted for therapeutic intervention by drugs like metformin and rapamycin.
Mutations in the alpha-synuclein (alphaSYN) gene are associated with rare cases of familial Parkinson's disease, and alphaSYN is a major component of Lewy bodies and Lewy neurites. Here we have ...investigated the localization of wild-type and mutant A30PalphaSYN as well as betaSYN at the cellular and subcellular level. Our direct comparative study demonstrates extensive synaptic colocalization of alphaSYN and betaSYN in human and mouse brain. In a sucrose gradient equilibrium centrifugation assay, a portion of betaSYN floated into lower density fractions, which also contained the synaptic vesicle marker synaptophysin. Likewise, wild-type and A30PalphaSYN were found in floating fractions. Subcellular fractionation of mouse brain revealed that both alphaSYN and betaSYN were present in synaptosomes. In contrast to synaptophysin, betaSYN and alphaSYN were recovered from the soluble fraction upon lysis of the synaptosomes. Synaptic colocalization of alphaSYN and betaSYN was directly visualized by confocal microscopy of double-stained human brain sections. The Parkinson's disease-associated human mutant A30PalphaSYN was found to colocalize with betaSYN and synaptophysin in synapses of transgenic mouse brain. However, in addition to their normal presynaptic localization, transgenic wild-type and A30PalphaSYN abnormally accumulated in neuronal cell bodies and neurites throughout the brain. Thus, mutant A30PalphaSYN does not fail to be transported to synapses, but its transgenic overexpression apparently leads to abnormal cellular accumulations.
Immunotherapy against alpha-synuclein (α-syn) is a promising novel treatment strategy for Parkinson's disease (PD) and related α-synucleinopathies. We have previously shown that systemic treatment ...with the monoclonal oligomer/protofibril-selective antibody mAb47 targeting cytotoxic α-syn leads to reduced central nervous system levels of such species as well as an indication of reduced late-stage symptoms in aged (Thy-1)-hA30P α-syn transgenic mice.
Here, we performed an early-onset long-term treatment study with this antibody to evaluate effects on brain pathology and behavioral outcomes in the same mouse model. Compared to the placebo group, the treatment strongly reduced phosphorylated α-syn (pS129 α-syn) pathology in the upper brain stem. Moreover, a preserved recognition memory and risk assessment behavior could be seen in antibody-treated mice at six months of age, even although these effects were no longer significant at eleven months of age. Importantly, no evidence of inflammatory responses or other potential toxic effects was seen with the treatment. Taken together, this study supports the strategy to target α-syn oligomers/protofibrils with monoclonal antibodies to counteract early symptoms and slow down the progression of PD and other α-synucleinopathies.
PDF
