Research News

Although the practice of molecular medicine has taken enormous strides in recent years—as attested to by a wave of approvals of antisense oligonucleotide (ASO) therapies as well as the first CRISPR-based therapy—neurodegenerative diseases, such as prion disease, Huntington’s disease, Alzheimer’s disease, and Parkinson’s disease, remain a difficult challenge. Toxic protein aggregation has been implicated in neurodegeneration, pointing to gene silencing as a broadly applicable therapeutic strategy. Although ASOs and CRISPR-based silencing offer potential to suppress the expression of pathogenic proteins, efforts have not yet been successful. On page 1421 of this issue, Neumann et al. (1) report a new epigenetic editor that can silence the expression of prion protein (PrP) in the brains of mice and offers a fresh approach to the treatment of neurodegenerative diseases.

https://www.science.org/doi/10.1126/science.ado7082

https://www.science.org/doi/10.1126/science.adq3334

https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(24)00218-9/fulltext

Summary: “Overall, our finding that selenium metabolism is involved in mediating the exercise-induced increase in adult hippocampal neurogenesis demonstrates how systemic or environmental factors can regulate adult neurogenesis and hence plasticity in the DG. This could have far-reaching implications, as the activity-dependency of adult hippocampal neurogenesis is one of its key features and central to modern concepts of how adult-generated neurons provide life-long adaptability to the hippocampus in both health and disease. The identification of the mechanism underlying the exercise-induced increase in adult neurogenesis could facilitate the discovery of novel therapeutic interventions (including dietary selenium supplementation), which could be used to mimic the beneficial effects of exercise on cognitive function. Given that selenium is a cheap, readily available dietary supplement that is found in a number of commonly eaten foods, such as nuts, grains, and dairy products, it could easily be boosted in the diet of elderly people. This is particularly important for the treatment of individuals who are unable to exercise due to advanced age, frailty, or disability.”

Leiter O, Zhuo Z, Rust R, Wasielewska JM, Grönnert L, Kowal S, Overall RW, Adusumilli VS, Blackmore DG, Southon A, Ganio K, McDevitt CA, Rund N, Brici D, Mudiyan IA, Sykes AM, Rünker AE, Zocher S, Ayton S, Bush AI, Bartlett PF, Hou ST, Kempermann G, Walker TL. Selenium mediates exercise-induced adult neurogenesis and reverses learning deficits induced by hippocampal injury and aging. Cell Metab. 2023 Jun 6;35(6):1085. doi: 10.1016/j.cmet.2023.04.019. Erratum for: Cell Metab. 2022 Mar 1;34(3):408-423.e8. doi: 10.1016/j.cmet.2022.01.005. PMID: 37285804.

https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00005-5

Abstract:

Dyslexia and developmental language disorders are important learning difficulties. However, their genetic basis remains poorly understood, and most genetic studies were performed on Europeans. There is a lack of genome-wide association studies (GWAS) on literacy phenotypes of Chinese as a native language and English as a second language (ESL) in a Chinese population. In this study, we conducted GWAS on 34 reading/language-related phenotypes in Hong Kong Chinese bilingual children (including both twins and singletons; total N = 1046). We performed association tests at the single-variant, gene, and pathway levels. In addition, we tested genetic overlap of these phenotypes with other neuropsychiatric disorders, as well as cognitive performance (CP) and educational attainment (EA) using polygenic risk score (PRS) analysis. Totally 5 independent loci (LD-clumped at r² = 0.01; MAF > 0.05) reached genome-wide significance (p < 5e-08; filtered by imputation quality metric Rsq>0.3 and having at least 2 correlated SNPs (r² > 0.5) with p < 1e-3). The loci were associated with a range of language/literacy traits such as Chinese vocabulary, character and word reading, and rapid digit naming, as well as English lexical decision. Several SNPs from these loci mapped to genes that were reported to be associated with EA and other neuropsychiatric phenotypes, such as MANEA and PLXNC1. In PRS analysis, EA and CP showed the most consistent and significant polygenic overlap with a variety of language traits, especially English literacy skills. To summarize, this study revealed the genetic basis of Chinese and English abilities in a group of Chinese bilingual children. Further studies are warranted to replicate the findings.

Lin YP, Shi Y, Zhang R, Xue X, Rao S, Yin L, Lui KFH, Pan DJ, Maurer U, Choy KW, Paracchini S, McBride C, So HC. A genome-wide association study of Chinese and English language phenotypes in Hong Kong Chinese children. NPJ Sci Learn. 2024 Mar 27;9(1):26. doi: 10.1038/s41539-024-00229-7. PMID: 38538593; PMCID: PMC10973362.

https://pubmed.ncbi.nlm.nih.gov/38538593/

See also:

Chung CY, Pan DJ, Paracchini S, Jiang W, So HC, McBride C, Maurer U, Zheng M, Choy KW. Dyslexia-related loci are significantly associated with language and literacy in Chinese-English bilingual Hong Kong Chinese twins. Hum Genet. 2023 Oct;142(10):1519-1529. doi: 10.1007/s00439-023-02594-6. Epub 2023 Sep 5. PMID: 37668838.

https://pubmed.ncbi.nlm.nih.gov/37668838/

Abstract:  Synergistic interactions between human herpesvirus 6A (HHV-6A) and Epstein-Barr virus (EBV) are hypothesized in the etiopathogenesis of multiple sclerosis (MS). This study investigated if HHV-6A and EBV seroreactivities interact regarding the risk of developing MS. Antibodies against viral antigens were analyzed in biobank samples from 670 individuals who later developed MS and matched controls. Additive interactions were analyzed. A significant interaction between HHV-6A and EBNA-1 seroreactivities was observed in study participants above the median age of 24.9 years (attributable proportion due to interaction = 0.45). This finding supports the hypothesis that HHV-6A and EBV infections interact in MS development.

Grut V, Biström M, Salzer J, Stridh P, Jons D, Gustafsson R, Huang J, Bergström T, Kockum I, Waterboer T, Olsson T, Sundström P: Interactions between High Seroreactivity to Human Herpes Virus 6A and Epstein-Barr Virus in MS Development: A Presymptomatic Case-Control Study. Ann Neurol. 2024 Jun 11. doi: 10.1002/ana.27009. Epub ahead of print. PMID: 38860471.

https://pubmed.ncbi.nlm.nih.gov/38860471/

Abstract:

Autoimmune conditions underlie some cases of psychosis. Scientists are expanding their search for patients, who often benefit from treatment.

Stone R. The inflamed brain. Science. 2024 May 17;384(6697):728-733. doi: 10.1126/science.adq4311. Epub 2024 May 16. PMID: 38753793.

https://pubmed.ncbi.nlm.nih.gov/38753793/

https://www.frontiersin.org/articles/10.3389/fncel.2020.00274

https://www.frontiersin.org/articles/10.3389/fncel.2020.00274

Abstract :  Heat stress exposure in intermittent heat waves and subsequent exposure during war theaters pose a clinical challenge that can lead to multi-organ dysfunction and long-term complications in the elderly. Using an aged mouse model and high-throughput sequencing, this study investigated the molecular dynamics of the liver-brain connection during heat stress exposure. Distinctive gene expression patterns induced by periodic heat stress emerged in both brain and liver tissues. An altered transcriptome profile showed heat stress-induced altered acute phase response pathways, causing neural, hepatic, and systemic inflammation and impaired synaptic plasticity. Results also demonstrated that proinflammatory molecules such as S100B, IL-17, IL-33, and neurological disease signaling pathways were upregulated, while protective pathways like aryl hydrocarbon receptor signaling were downregulated. In parallel, Rantes, IRF7, NOD1/2, TREM1, and hepatic injury signaling pathways were upregulated. Furthermore, current research identified Orosomucoid 2 (ORM2) in the liver as one of the mediators of the liver-brain axis due to heat exposure. In conclusion, the transcriptome profiling in elderly heat-stressed mice revealed a coordinated network of liver-brain axis pathways with increased hepatic ORM2 secretion, possibly due to gut inflammation and dysbiosis. The above secretion of ORM2 may impact the brain through a leaky blood-brain barrier, thus emphasizing intricate multi-organ crosstalk.

Roy S, Saha P, Bose D, Trivedi A, More M, Lin C, Wu J, Oakes M, Chatterjee S. Periodic heat waves-induced neuronal etiology in the elderly is mediated by gut-liver-brain axis: a transcriptome profiling approach. Sci Rep. 2024 May 8;14(1):10555. doi: 10.1038/s41598-024-60664-9. PMID: 38719902; PMCID: PMC11079080.

https://pubmed.ncbi.nlm.nih.gov/38719902/

Abstract:    Polypropylene (PP) is suitable for a broad range of applications and represents the most extensively utilized plastic in food packaging. Micro- and nano-PP plastics are prevalent categories of microplastics (MPs). However, the majority of MPs particles currently utilized in laboratory studies are man-made polystyrene (PS) spheres, and there has been limited research on micrometer- and nanoscale PP plastic particles. This study aims to employ a top-down approach in crafting micro/nanoparticle (M/NPs) models of PP particles, ensuring their enhanced relevance to real-world environments. Micro/nano PP particles, featuring a negatively charged particle size ranging from 203 to 2101 nm, were synthesized through variations in solution concentration and volume. Simultaneously, the devised MPs model was employed to develop a Raman-based qualitative and quantitative detection method for micro/nano PP particles, considering diverse sizes and concentrations. This method integrates Raman spectroscopy and microscopy to measure PP particles with varying sizes, utilizing the coffee ring effect. The Limit of detection (LOD) for 203 nm PP reached 31.25 μg/mL, while those for 382 to 2101 nm PP were approximately 3.9 μg/mL. The method underwent quantitative analysis by introducing 203 nm PP nanospheres into real food media (i.e., tea beverages, tea leaves), revealing a minimum LOD of approximately 31.25 μg/mL.

Xiang T, Sun Y, Ding D, Yao W, Yu Z, Xie Y. Microscopic Raman-based rapid detection of submicron/nano polypropylene plastics in tea and tea beverages. Food Chem. 2024 May 16;454:139657. doi: 10.1016/j.foodchem.2024.139657. Epub ahead of print. PMID: 38810455.

https://pubmed.ncbi.nlm.nih.gov/38810455/

Sigma non-opioid intracellular receptor 1 (Sigma-1R) is an intracellular chaperone protein residing on the endoplasmic reticulum at the mitochondrial-associated membrane (MAM) region. Sigma-1R is abundant in the brain and is involved in several physiological processes as well as in various disease states. The role of Sigma-1R at the blood-brain barrier (BBB) is incompletely characterized. In this study, the effect of Sigma-1R activation was investigated in vitro on rat brain microvascular endothelial cells (RBMVEC), an important component of the blood-brain barrier (BBB), and in vivo on BBB permeability in rats. The Sigma-1R agonist PRE-084 produced a dose-dependent increase in mitochondrial calcium, and mitochondrial and cytosolic reactive oxygen species (ROS) in RBMVEC. PRE-084 decreased the electrical resistance of the RBMVEC monolayer, measured with the electric cell-substrate impedance sensing (ECIS) method, indicating barrier disruption. These effects were reduced by pretreatment with Sigma-1R antagonists, BD 1047 and NE 100. In vivo assessment of BBB permeability in rats indicates that PRE-084 produced a dose-dependent increase in brain extravasation of Evans Blue and sodium fluorescein brain; the effect was reduced by the Sigma-1R antagonists. Immunocytochemistry studies indicate that PRE-084 produced a disruption of tight and adherens junctions and actin cytoskeleton. The brain microcirculation was directly visualized in vivo in the prefrontal cortex of awake rats with a miniature integrated fluorescence microscope (aka, miniscope; Doric Lenses Inc.). Miniscope studies indicate that PRE-084 increased sodium fluorescein extravasation in vivo. Taken together, these results indicate that Sigma-1R activation promoted oxidative stress and increased BBB permeability.

Brailoiu E, Barr JL, Wittorf HN, Inan S, Unterwald EM, Brailoiu GC. Modulation of the Blood-Brain Barrier by Sigma-1R Activation. Int J Mol Sci. 2024 May 9;25(10):5147. doi: 10.3390/ijms25105147. PMID: 38791182; PMCID: PMC11121402.

https://pubmed.ncbi.nlm.nih.gov/38791182/

Abstract

Background: Previous studies have shown that brain volume is negatively associated with cigarette smoking, but there is an ongoing debate about whether smoking causes lowered brain volume or a lower brain volume is a risk factor for smoking. We address this debate through multiple methods that evaluate directionality: Bradford Hill’s criteria, which are commonly used to understand a causal relationship in epidemiological studies, and mediation analysis.  Methods: In 32,094 participants of European descent from the UK Biobank dataset, we examined the relationship between a history of daily smoking and brain volumes, as well as an association of genetic risk score to ever smoking with brain volume.  Results: A history of daily smoking was strongly associated with decreased brain volume, and a history of heavier smoking was associated with a greater decrease in brain volume. The strongest association was between total gray matter volume and a history of daily smoking (effect size = −2964 mm³, p = 2.04 × 10⁻¹⁶), and there was a dose-response relationship with more pack years smoked associated with a greater decrease in brain volume. A polygenic risk score for smoking initiation was strongly associated with a history of daily smoking (effect size = 0.05, p = 4.20 × 10⁻⁸⁴), but only modestly associated with total gray matter volume (effect size = −424 mm³, p = .01). Mediation analysis indicated that a history of daily smoking mediated the relationship between the smoking initiation polygenic risk score and total gray matter volume. Conclusions: A history of daily smoking is strongly associated with a decreased total brain volume.

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Chang Y, Thornton V, Chaloemtoem A, Anokhin AP, Bijsterbosch J, Bogdan R, Hancock DB, Johnson EO, Bierut LJ. Investigating the Relationship Between Smoking Behavior and Global Brain Volume. Biol Psychiatry Glob Open Sci. 2023 Oct 6;4(1):74-82. doi: 10.1016/j.bpsgos.2023.09.006. PMID: 38130847; PMCID: PMC10733671.

https://www.bpsgos.org/article/S2667-1743(23)00136-2/fulltext