CSF Protein Level of Neurotransmitter Secretion, Synaptic Plasticity, and Autophagy in PD and DLB

BACKGROUND: Molecular pathways associated with α-synuclein proteostasis have been detected in genetic studies and in cell models and include autophagy, ubiquitin-proteasome system, mitochondrial homeostasis, and synaptic plasticity. However, we lack biomarkers that are representative for these pathways in human biofluids. OBJECTIVE: The objective of this study was to evaluate CSF protein profiles of pathways related to α-synuclein proteostasis. METHODS: We assessed CSF protein profiles associated with neurotransmitter secretion, synapse plasticity, and autophagy in 2 monocentric cohorts with α-synucleinopathy (385 PD patients and 67 DLB patients). We included 80 PD patients and 17 DLB patients with variants in the glucocerebrosidase gene to serve as proxy for accelerated α-synuclein pathology with pronounced clinical trajectories. RESULTS: (1) Proteins associated with neurotransmitter secretion, synaptic plasticity, and endolysosomal autophagy were lower in PD and DLB patients compared with healthy controls. (2) These patterns were more pronounced in DLB than in PD patients, accentuated by GBA variant status in both entities. (3) CSF levels of these proteins were positively associated with CSF levels of total α-synuclein, with lower levels of proteostasis proteins related to lower levels of total α-synuclein. (4) These findings could be confirmed longitudinally. PD patients with low CSF profiles of proteostasis proteins showed lower CSF levels of α-synuclein longitudinally compared with PD patients with a normal proteostasis profile. CONCLUSION: CSF proteins associated with neurotransmitter secretion, synaptic plasticity, and endolysosomal autophagy might serve as biomarkers related to α-synuclein proteostasis in PD and DLB

Association between CSF alpha-synuclein seeding activity and genetic status in Parkinson’s disease and dementia with Lewy bodies

The clinicopathological heterogeneity in Lewy-body diseases (LBD) highlights the need for pathology-driven biomarkers in-vivo. Misfolded alpha-synuclein (α-Syn) is a lead candidate based on its crucial role in disease pathophysiology. Real-time quaking-induced conversion (RT-QuIC) analysis of CSF has recently shown high sensitivity and specificity for the detection of misfolded α-Syn in patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In this study we performed the CSF RT-QuIC assay in 236 PD and 49 DLB patients enriched for different genetic forms with mutations in GBA, parkin, PINK1, DJ1, and LRRK2. A subgroup of 100 PD patients was also analysed longitudinally. We correlated kinetic seeding parameters of RT-QuIC with genetic status and CSF protein levels of molecular pathways linked to α-Syn proteostasis. Overall, 85% of PD and 86% of DLB patients showed positive RT-QuIC α-Syn seeding activity. Seeding profiles were significantly associated with mutation status across the spectrum of genetic LBD. In PD patients, we detected positive α-Syn seeding in 93% of patients carrying severe GBA mutations, in 78% with LRRK2 mutations, in 59% carrying heterozygous mutations in recessive genes, and in none of those with bi-allelic mutations in recessive genes. Among PD patients, those with severe GBA mutations showed the highest seeding activity based on RT-QuIC kinetic parameters and the highest proportion of samples with 4 out of 4 positive replicates. In DLB patients, 100% with GBA mutations showed positive α-Syn seeding compared to 79% of wildtype DLB. Moreover, we found an association between α-Syn seeding activity and reduced CSF levels of proteins linked to α-Syn proteostasis, specifically lysosome-associated membrane glycoprotein 2 and neurosecretory protein VGF. These findings highlight the value of α-Syn seeding activity as an in-vivo marker of Lewy-body pathology and support its use for patient stratification in clinical trials targeting α-Syn

IL-10 transcription is negatively regulated by BAF180, a component of the SWI/SNF chromatin remodeling enzyme

<p>Abstract</p> <p>Background</p> <p>SWI/SNF chromatin remodeling enzymes play a critical role in the development of T helper lymphocytes, including Th2 cells, and directly program chromatin structure at Th2 cytokine genes. Different versions of SWI/SNF complexes, including BAF and PBAF, have been described based on unique subunit composition. However, the relative role of BAF and PBAF in Th cell function and cytokine expression has not been reported.</p> <p>Results</p> <p>Here we examine the role of the PBAF SWI/SNF complex in Th cell development and gene expression using mice deficient for a PBAF-specific component, BAF180. We find that T cell development in the thymus and lymphoid periphery is largely normal when the BAF180 gene is deleted late in thymic development. However, BAF180-deficient Th2 cells express high levels of the immunoregulatory cytokine IL-10. BAF180 binds directly to regulatory elements in the Il-10 locus but is replaced by BAF250 BAF complexes in the absence of BAF180, resulting in increased histone acetylation and CBP recruitment to the IL-10 locus.</p> <p>Conclusions</p> <p>These results demonstrate that BAF180 is a repressor of IL-10 transcription in Th2 cells and suggest that the differential recruitment of different SWI/SNF subtypes can have direct consequences on chromatin structure and gene transcription.</p

Magnetically-Regulated Fragmentation Induced by Nonlinear Flows and Ambipolar Diffusion

We present a parameter study of simulations of fragmentation regulated by gravity, magnetic fields, ambipolar diffusion, and nonlinear flows. The thin-sheet approximation is employed with periodic lateral boundary conditions, and the nonlinear flow field ("turbulence") is allowed to freely decay. In agreement with previous results in the literature, our results show that the onset of runaway collapse (formation of the first star) in subcritical clouds is significantly accelerated by nonlinear flows in which a large-scale wave mode dominates the power spectrum. In addition, we find that a power spectrum with equal energy on all scales also accelerates collapse, but by a lesser amount. For a highly super-Alfvenic initial velocity field with most power on the largest scales, the collapse occurs promptly during the initial compression wave. However, for trans-Alfvenic perturbations, a subcritical magnetic field causes a rebound from the initial compression, and the system undergoes several oscillations before runaway collapse occurs. Models that undergo prompt collapse have highly supersonic infall motions at the core boundaries. Cores in magnetically subcritical models with trans-Alfvenic initial perturbations also pick up significant systematic speeds by inheriting motions associated with magnetically-driven oscillations. Core mass distributions are much broader than in models with small-amplitude initial perturbations, although the disturbed structure of cores that form due to nonlinear flows does not guarantee subsequent monolithic collapse. Our simulations also demonstrate that significant power can (if present initially) be maintained with negligible dissipation in large-scale compressive modes of a magnetic thin sheet, in the limit of perfect flux freezing.Comment: v2, 26 pages, 12 figures, to appear in New Astronomy, animations at http://www.astro.uwo.ca/~basu/pb.ht

Parkinson’s disease: evolution of cognitive impairment and CSF Aβ₁−₄₂ profiles in a prospective longitudinal study

OBJECTIVE: To evaluate the evolution of cognitive impairment in relation to cerebrospinal fluid (CSF) profiles of amyloid-β (Aβ), total-Tau and phosphorylated-Tau in Parkinson’s disease (PD). METHODS: Prospective, longitudinal, observational study up to 10 years with follow-up every 2  years. We assessed CSF profiles in 415 patients with sporadic PD (median age 66; 63% men) and 142 healthy controls (median age 62; 43% men). RESULTS: Patients with PD with low CSF Aβ₁−₄₂ levels at baseline were more often cognitively impaired than patients with intermediate and high Aβ₁−₄₂ levels. Sixty-seven per cent of the patients with low Aβ₁−₄₂ levels at baseline and normal cognition developed cognitive impairment during follow-up, compared with 41% and 37% of patients having intermediate and high CSF Aβ₁−₄₂ levels. Kaplan-Meier survival curves and Cox regression revealed that patients with low CSF Aβ₁−₄₂ levels at baseline developed cognitive impairment more frequently and earlier during follow-up. CONCLUSION: We conclude that in patients with sporadic PD, low levels of Aβ₁−₄₂ are associated with a higher risk of developing cognitive impairment earlier in the disease process at least in a subgroup of patients

FGF10 maintains distal lung bud epithelium and excessive signaling leads to progenitor state arrest, distalization, and goblet cell metaplasia

<p>Abstract</p> <p>Background</p> <p>Interaction with the surrounding mesenchyme is necessary for development of endodermal organs, and Fibroblast growth factors have recently emerged as mesenchymal-expressed morphogens that direct endodermal morphogenesis. The fibroblast growth factor 10 (<it>Fgf10</it>) null mouse is characterized by the absence of lung bud development. Previous studies have shown that this requirement for <it>Fgf10 </it>is due in part to its role as a chemotactic factor during branching morphogenesis. In other endodermal organs <it>Fgf10 </it>also plays a role in regulating differentiation.</p> <p>Results</p> <p>Through gain-of-function analysis, we here find that FGF10 inhibits differentiation of the lung epithelium and promotes distalization of the embryonic lung. Ectopic expression of FGF10 in the lung epithelium caused impaired lung development and perinatal lethality in a transgenic mouse model. Lung lobes were enlarged due to increased interlobular distance and hyperplasia of the airway epithelium. Differentiation of bronchial and alveolar cell lineages was inhibited. The transgenic epithelium consisted predominantly of proliferating progenitor-like cells expressing Pro-surfactant protein C, TTF1, PEA3 and Clusterin similarly to immature distal tip cells. Strikingly, goblet cells developed within this arrested epithelium leading to goblet cell hyperplasia.</p> <p>Conclusion</p> <p>We conclude that FGF10 inhibits terminal differentiation in the embryonic lung and maintains the distal epithelium, and that excessive levels of FGF10 leads to metaplastic differentiation of goblet cells similar to that seen in chronic inflammatory diseases.</p

Differentiation-Inducing Factor-1 and -2 Function also as Modulators for Dictyostelium Chemotaxis

BackgroundIn the early stages of development of the cellular slime mold Dictyostelium discoideum, chemotaxis toward cAMP plays a pivotal role in organizing discrete cells into a multicellular structure. In this process, a series of signaling molecules, such as G-protein-coupled cell surface receptors for cAMP, phosphatidylinositol metabolites, and cyclic nucleotides, function as the signal transducers for controlling dynamics of cytoskeleton. Differentiation-inducing factor-1 and -2 (DIF-1 and DIF-2) were originally identified as the factors (chlorinated alkylphenones) that induce Dictyostelium stalk cell differentiation, but it remained unknown whether the DIFs had any other physiologic functions.Methodology/Principal FindingsTo further elucidate the functions of DIFs, in the present study we investigated their effects on chemotaxis under various conditions. Quite interestingly, in shallow cAMP gradients, DIF-1 suppressed chemotaxis whereas DIF-2 promoted it greatly. Analyses with various mutants revealed that DIF-1 may inhibit chemotaxis, at least in part, via GbpB (a phosphodiesterase) and a decrease in the intracellular cGMP concentration ([cGMP]i). DIF-2, by contrast, may enhance chemotaxis, at least in part, via RegA (another phosphodiesterase) and an increase in [cGMP]i. Using null mutants for DimA and DimB, the transcription factors that are required for DIF-dependent prestalk differentiation, we also showed that the mechanisms for the modulation of chemotaxis by DIFs differ from those for the induction of cell differentiation by DIFs, at least in part.Conclusions/SignificanceOur findings indicate that DIF-1 and DIF-2 function as negative and positive modulators for Dictyostelium chemotaxis, respectively. To our knowledge, this is the first report in any organism of physiologic modulators (small molecules) for chemotaxis having differentiation-inducing activity

Thermal Evolution of the Proton Irradiated Structure in Tungsten–5 wt% Tantalum

We have monitored the thermal evolution of the proton irradiated structure of W–5 wt% Ta alloy by in-situ annealing in a transmission electron microscope at fusion reactor temperatures of 500–1300 °C. The interstitial-type a/2 dislocation loops emit self-interstitial atoms and glide to the free sample surface during the early stages of annealing. The resultant vacancy excess in the matrix originates vacancy-type a/2 dislocation loops that grow by loop and vacancy absorption in the temperature range of 600–900 °C. Voids form at 1000 °C, by either vacancy absorption or loop collapse, and grow progressively up to 1300 °C. Tantalum delays void formation by a vacancy-solute trapping mechanism