Publications by authors named "Simon Hornung"

8 Publications

  • Page 1 of 1

α-Synuclein in blood exosomes immunoprecipitated using neuronal and oligodendroglial markers distinguishes Parkinson's disease from multiple system atrophy.

Acta Neuropathol 2021 09 15;142(3):495-511. Epub 2021 May 15.

Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.

The diagnosis of Parkinson's disease (PD) and atypical parkinsonian syndromes is difficult due to the lack of reliable, easily accessible biomarkers. Multiple system atrophy (MSA) is a synucleinopathy whose symptoms often overlap with PD. Exosomes isolated from blood by immunoprecipitation using CNS markers provide a window into the brain's biochemistry and may assist in distinguishing between PD and MSA. Thus, we asked whether α-synuclein (α-syn) in such exosomes could distinguish among healthy individuals, patients with PD, and patients with MSA. We isolated exosomes from the serum or plasma of these three groups by immunoprecipitation using neuronal and oligodendroglial markers in two independent cohorts and measured α-syn in these exosomes using an electrochemiluminescence ELISA. In both cohorts, α-syn concentrations were significantly lower in the control group and significantly higher in the MSA group compared to the PD group. The ratio between α-syn concentrations in putative oligodendroglial exosomes compared to putative neuronal exosomes was a particularly sensitive biomarker for distinguishing between PD and MSA. Combining this ratio with the α-syn concentration itself and the total exosome concentration, a multinomial logistic model trained on the discovery cohort separated PD from MSA with an AUC = 0.902, corresponding to 89.8% sensitivity and 86.0% specificity when applied to the independent validation cohort. The data demonstrate that a minimally invasive blood test measuring α-syn in blood exosomes immunoprecipitated using CNS markers can distinguish between patients with PD and patients with MSA with high sensitivity and specificity. Future optimization and validation of the data by other groups would allow this strategy to become a viable diagnostic test for synucleinopathies.
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http://dx.doi.org/10.1007/s00401-021-02324-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357708PMC
September 2021

Correction to: The molecular tweezer CLR01 improves behavioral deficits and reduces tau pathology in P301S-tau transgenic mice.

Alzheimers Res Ther 2021 Apr 22;13(1):88. Epub 2021 Apr 22.

Department of Neurology, David Geffen School of Medicine, University of California, Gordon Neuroscience Research Building, Room 451, 635 Charles E. Young Drive South, Los Angeles, CA, 90095-7334, USA.

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http://dx.doi.org/10.1186/s13195-021-00823-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063374PMC
April 2021

The molecular tweezer CLR01 improves behavioral deficits and reduces tau pathology in P301S-tau transgenic mice.

Alzheimers Res Ther 2021 01 4;13(1). Epub 2021 Jan 4.

Department of Neurology, David Geffen School of Medicine, University of California, Gordon Neuroscience Research Building, Room 451, 635 Charles E. Young Drive South, Los Angeles, CA, 90095-7334, USA.

Background: Molecular tweezers (MTs) are broad-spectrum inhibitors of abnormal protein aggregation. A lead MT, called CLR01, has been demonstrated to inhibit the aggregation and toxicity of multiple amyloidogenic proteins in vitro and in vivo. Previously, we evaluated the effect of CLR01 in the 3 × Tg mouse model of Alzheimer's disease, which overexpresses mutant human presenilin 1, amyloid β-protein precursor, and tau and found that subcutaneous administration of the compound for 1 month led to a robust reduction of amyloid plaques, neurofibrillary tangles, and microgliosis. CLR01 also has been demonstrated to inhibit tau aggregation in vitro and tau seeding in cell culture, yet because in Alzheimer's disease (AD) and in the 3 × Tg model, tau hyperphosphorylation and aggregation are thought to be downstream of Aβ insults, the study in this model left open the question whether CLR01 affected tau in vivo directly or indirectly.

Methods: To determine if CLR01 could ameliorate tau pathology directly in vivo, we tested the compound similarly using the P301S-tau (line PS19) mouse model. Mice were administered 0.3 or 1.0 mg/kg per day CLR01 and tested for muscle strength and behavioral deficits, including anxiety- and disinhibition-like behavior. Their brains then were analyzed by immunohistochemical and biochemical assays for pathological forms of tau, neurodegeneration, and glial pathology.

Results: CLR01 treatment ameliorated muscle-strength deterioration, anxiety-, and disinhibition-like behavior. Improved phenotype was associated with decreased levels of pathologic tau forms, suggesting that CLR01 exerts a direct effect on tau in vivo. Limitations of the study included a relatively short treatment period of the mice at an age in which full pathology is not yet developed. In addition, high variability in this model lowered the statistical significance of the findings of some outcome measures.

Conclusions: The findings suggest that CLR01 is a particularly attractive candidate for the treatment of AD because it targets simultaneously the two major pathogenic proteins instigating and propagating the disease, amyloid β-protein (Aβ), and tau, respectively. In addition, our study suggests that CLR01 can be used for the treatment of other tauopathies in the absence of amyloid pathology.
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http://dx.doi.org/10.1186/s13195-020-00743-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784007PMC
January 2021

A century later: Adaptive plasticity and rapid evolution contribute to geographic variation in invasive mosquitofish.

Sci Total Environ 2020 Jul 18;726:137908. Epub 2020 Mar 18.

Department of Aquatic Ecotoxicology, Johann Wolfgang Goethe University Frankfurt am Main, Frankfurt am Main, Germany. Electronic address:

One century after their introduction to Europe, eastern mosquitofish (Gambusia holbrooki) represent a natural experiment to determine the relative contributions of adaptive plasticity and rapid evolutionary change in creating large-scale geographic variation in phenotypes. We evaluated the population-genetic structure and invasion history based on allele length polymorphisms of 15 nuclear microsatellites, which we quantified for N = 660 individuals from 23 populations sampled in 2013 across the invasive range of G. holbrooki in Europe. We analysed body-shape and life-history variation in N = 1331 individuals from 36 populations, sampled in 2013 and 2017, and tested heritability of phenotypic differences in a subset of four populations using a common-garden experiment. The genetic structure of wild-caught individuals suggested a single introduction for all European mosquitofish, which were genetically impoverished compared to their native counterparts. We found some convergent patterns of phenotypic divergence across native and invasive climatic gradients (e.g., increased body size in colder/more northern populations); however, several phenotypic responses were not consistent between sampling years, pointing towards plastic phenotypes. Our analysis of common-garden reared individuals uncovered moderate heritability estimates only for two measures of male body size (intraclass correlation coefficient, ICC = 0.628 and 0.556) and offspring fat content (ICC = 0.734), while suggesting high levels of plasticity in most other phenotypic traits (ICC ≤ 0.407). Our results highlight the importance of phenotypic plasticity in invasive species during range expansions and demonstrate that strong selective pressures-in this case towards increased body size in colder environments-simultaneously promote rapid evolutionary divergence.
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http://dx.doi.org/10.1016/j.scitotenv.2020.137908DOI Listing
July 2020

CNS-Derived Blood Exosomes as a Promising Source of Biomarkers: Opportunities and Challenges.

Front Mol Neurosci 2020 19;13:38. Epub 2020 Mar 19.

Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.

Eukaryotic cells release different types of extracellular vesicles (EVs) including exosomes, ectosomes, and microvesicles. Exosomes are nanovesicles, 30-200 nm in diameter, that carry cell- and cell-state-specific cargo of proteins, lipids, and nucleic acids, including mRNA and miRNA. Recent studies have shown that central nervous system (CNS)-derived exosomes may carry amyloidogenic proteins and facilitate their cell-to-cell transfer, thus playing a critical role in the progression of neurodegenerative diseases, such as tauopathies and synucleinopathies. CNS-derived exosomes also have been shown to cross the blood-brain-barrier into the bloodstream and therefore have drawn substantial attention as a source of biomarkers for various neurodegenerative diseases as they can be isolated via a minimally invasive blood draw and report on the biochemical status of the CNS. However, although isolating specific brain-cell-derived exosomes from the blood is theoretically simple and the approach has great promise, practical details are of crucial importance and may compromise the reproducibility and utility of this approach, especially when different laboratories use different protocols. In this review we discuss the role of exosomes in neurodegenerative diseases, the usefulness of CNS-derived blood exosomes as a source of biomarkers for these diseases, and practical challenges associated with the methodology of CNS-derived blood exosomes and subsequent biomarker analysis.
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http://dx.doi.org/10.3389/fnmol.2020.00038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096580PMC
March 2020

An improved process for the production of highly purified recombinant thaumatin tagged-variants.

Food Chem 2017 Dec 13;237:825-832. Epub 2017 Jun 13.

School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia. Electronic address:

The sweetest tasting molecule known is the protein thaumatin, first isolated from the katemfe fruit, Thaumatococcus daniellii. Thaumatin is used in the food and beverage industry as a low-calorie sugar substitute. Thaumatin interacts with taste receptors in the oral cavity eliciting a persistent sweet taste and a bitter, liquorice flavor. Recombinant thaumatin was expressed in Pichia pastoris and through a co-expression strategy with a molecular chaperone, yields of one engineered thaumatin variant increased by greater than two-fold. A detailed purification strategy for thaumatin is reported resulting in a homogenous sample recovered at a yield of 42%. The recombinant thaumatins were extensively characterised using size exclusion chromatography for homogeneity, reversed-phase HPLC for purity (99%), peptide digest LC-MS/MS for sequence determination, and circular dichroism and tryptophan fluorescence spectroscopies for conformational characterisation. These new thaumatin variants are amenable for bioconjugation, providing chemical biology tools for thaumatin:taste receptor interaction studies.
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http://dx.doi.org/10.1016/j.foodchem.2017.06.018DOI Listing
December 2017

Homosexual behaviour increases male attractiveness to females.

Biol Lett 2013 Feb 12;9(1):20121038. Epub 2012 Dec 12.

Department of Ecology and Evolution, University of Frankfurt, Frankfurt am Main 60438, Germany.

Male homosexual behaviour-although found in most extant clades across the Animal Kingdom-remains a conundrum, as same-sex mating should decrease male reproductive fitness. In most species, however, males that engage in same-sex sexual behaviour also mate with females, and in theory, same-sex mating could even increase male reproductive fitness if males improve their chances of future heterosexual mating. Females regularly use social information to choose a mate; e.g. male attractiveness increases after a male has interacted sexually with a female (mate choice copying). Here, we demonstrate that males of the tropical freshwater fish Poecilia mexicana increase their attractiveness to females not only by opposite-sex, but likewise, through same-sex interactions. Hence, direct benefits for males of exhibiting homosexual behaviour may help explain its occurrence and persistence in species in which females rely on mate choice copying as one component of mate quality assessment.
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http://dx.doi.org/10.1098/rsbl.2012.1038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565526PMC
February 2013
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