Abstract:

Chronic low-grade inflammation and neuronal deregulation are two components of a smoldering disease activity that drives the progression of disability in people with multiple sclerosis (MS). Although several therapies exist to dampen the acute inflammation that drives MS relapses, therapeutic options to halt chronic disability progression are a major unmet clinical need. The development of such therapies is hindered by our limited understanding of the neuron-intrinsic determinants of resilience or vulnerability to inflammation. In this Review, we provide a neuron-centric overview of recent advances in deciphering neuronal response patterns that drive the pathology of MS. We describe the inflammatory CNS environment that initiates neurotoxicity by imposing ion imbalance, excitotoxicity and oxidative stress, and by direct neuro-immune interactions, which collectively lead to mitochondrial dysfunction and epigenetic dysregulation. The neuronal demise is further amplified by breakdown of neuronal transport, accumulation of cytosolic proteins and activation of cell death pathways. Continuous neuronal damage perpetuates CNS inflammation by activating surrounding glia cells and by directly exerting toxicity on neighbouring neurons. Further, we explore strategies to overcome neuronal deregulation in MS and compile a selection of neuronal actuators shown to impact neurodegeneration in preclinical studies. We conclude by discussing the therapeutic potential of targeting such neuronal actuators in MS, including some that have already been tested in interventional clinical trials.

Woo, M.S., Engler, J.B. & Friese, M.A. The neuropathobiology of multiple sclerosis. Nat. Rev. Neurosci. 25493–513 (2024). https://doi.org/10.1038/s41583-024-00823-z

https://www.nature.com/articles/s41583-024-00823-z

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Abstract: “MiR-142-3p has recently emerged as key factor in tailoring personalized treatments for multiple sclerosis (MS), a chronic autoimmune demyelinating disease of the central nervous system (CNS) with heterogeneous pathophysiology and an unpredictable course. With its involvement in a detrimental regulatory axis with interleukin-1beta (IL1β), miR-142-3p orchestrates excitotoxic synaptic alterations that significantly impact both MS progression and therapeutic outcomes. In this study, we investigated for the first time the influence of individual genetic variability on the miR-142-3p excitotoxic effect in MS. We specifically focused on the single-nucleotide polymorphism Val66Met (rs6265) of the brain-derived neurotrophic factor (BDNF) gene, known for its crucial role in CNS functioning. We assessed the levels of miR-142-3p and IL1β in cerebrospinal fluid (CSF) obtained from a cohort of 114 patients with MS upon diagnosis. By stratifying patients according to their genetic background, statistical correlations with clinical parameters were performed. Notably, in Met-carrier patients, we observed a decoupling of miR-142-3p levels from IL1β levels in the CSF, as well as from of disease severity (Expanded Disability Status Score, EDSS; Multiple Sclerosis Severity Score, MSSS; Age-Related Multiple Sclerosis Severity Score, ARMSS) and progression (Progression Index, PI). Our discovery of the interference between BDNF Val66Met polymorphism and the synaptotoxic IL1β-miR-142-3p axis, therefore hampering miR-142-3p action on MS course, provides valuable insights for further development of personalized medicine in the field.”

Dolcetti E, Musella A, Balletta S, Gilio L, Bruno A, Stampanoni Bassi M, Lauritano G, Buttari F, Fresegna D, Tartacca A, Mariani F, Palmerio F, Rovella V, Ferese R, Gambardella S, Giardina E, Finardi A, Furlan R, Mandolesi G, Centonze D, De Vito F. Interaction between miR-142-3p and BDNF Val/Met Polymorphism Regulates Multiple Sclerosis Severity. Int J Mol Sci. 2024 May 11;25(10):5253. doi: 10.3390/ijms25105253. PMID: 38791290; PMCID: PMC11121620.

https://pubmed.ncbi.nlm.nih.gov/38791290/

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Abstract:  “Multiple sclerosis (MS) is a condition characterized by inflammation in the central nervous system (CNS), impacting sensory, motor, and cognitive abilities. Globally, around three million individuals are affected by MS, with up to 97,000 cases in Iran attributed to genetic predispositions along with various environmental factors like smoking. Cognitive impairment affects a significant portion of patients, ranging from 45% to 70%. This study investigates the impact of regular aerobic swimming exercise for four weeks, mild cognitive impairment induced by encephalomyelitis, and their combination on the expression of microRNA-142-3p and its correlation with the release of brain-derived neurotrophic factor (BDNF) in relation to spatial memory. Twenty-one C57BL/6 mice were divided into three groups. RT-PCR was used for microRNA expression analysis, and BDNF levels were assessed via western blotting. Clinical scores and animal weights were monitored daily. EAE induction led to an increase in microRNA-142-3p expression and a decrease in BDNF levels compared to the control group. Exercise inversed them significantly, and improved spatial memory. Our findings indicate that engaging in regular swimming exercise can counteract the up-regulation of miR-142-3p in brain tissue, which likely contributes to mild cognitive impairment induced by MS. Additionally, the increase in BDNF following exercise appears to be associated with miR-142-3p and the enhancement of cognitive function. Thus, the therapeutic benefits of exercise, particularly in releasing BDNF to improve cognitive function in MS patients, warrant consideration. Lifestyle modifications have the potential to effectively modulate environmental influences and ethnicity, underscoring their significance in MS management.”

Banasadegh S, Shahrbanian S, Gharakhanlou R, Kordi MR, Mohammad Soltani B. Enhancing brain health: Swimming-induced BDNF release and epigenetic influence in MS female mouse models. J Ethn Subst Abuse. 2024 Jun 20:1-17. doi: 10.1080/15332640.2024.2365230. Epub ahead of print. PMID: 38900673.

https://pubmed.ncbi.nlm.nih.gov/38900673/

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Editor’s summary: “Vitamin B12 deficiency can lead to neurological deficits, sometimes in the absence of anemia, and mice and patients with mutations in the transcobalamin receptor CD320 do not develop anemia, suggesting that the mechanisms governing B12 uptake in different tissues are not fully understood. Here, Pluvinage and colleagues identified an autoantibody against CD320 in a patient with progressive neurological symptoms that blocked B12 uptake in endothelial cells and was associated with central but not peripheral vitamin B12 deficiency. The authors identified additional individuals with anti-CD320 autoantibodies and also found an association with neuropsychiatric systemic lupus erythematosus. The low-density lipoprotein receptor was identified as a noncanonical transcobalamin receptor in the periphery only, potentially explaining why anti-CD320 autoantibodies lead to central but not peripheral vitamin B12 deficiency. ”

Pluvinage JV et al. : Transcobalamin receptor antibodies in autoimmune vitamin B12 central deficiency. Science  Translational Medicine 16. (753): DOI: 10.1126/scitranslmed.adl3758 , June 26, 2024.

https://www.science.org/doi/10.1126/scitranslmed.adl3758

 

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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

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

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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

 

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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/

 

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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/

 

 

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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

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