Stephan Quintin, Zachary A Sorrentino, Yusuf Mehkri, Sai Sriram, Sydney Weisman, Caroline Grace Davidson, Grace M Lloyd, Eric Sung, John W Figg, Brandon Lucke-Wold
Neurotrauma, especially repetitive neurotrauma, is associated with the development of progressive neurodegeneration leading to chronic traumatic encephalopathy (CTE). Exposure to neurotrauma regularly occurs during sports and military service, often not requiring medical care. However, exposure to severe and/or repeated sub-clinical neurotrauma has been shown cause physical and psychological disability, leading to reduce life expectancy. Misfolding of proteins, or proteinopathy, is a pathological hallmark of CTE, in which chronic injury leads to local and diffuse protein aggregates. These aggregates are an overlapping feature of many neurodegenerative diseases such as CTE, Alzheimer's Disease, Parkinsons disease. Neurotrauma is also a significant risk factor for the development of these diseases, however the mechanism's underlying this association are not well understood. While phosphorylated tau aggregates are the primary feature of CTE, amyloid-beta, Transactive response DNA-binding protein 43 (TDP-43), and alpha-synuclein (αSyn) are also well documented. Aberrant misfolding of these proteins has been shown to disrupt brain homeostasis leading to neurodegeneration in a disease dependent manor. In CTE, the interaction between proteinopathies and their associated neurodegeneration is a current area of study. Here we provide an update on current literature surrounding the prevalence, characteristics, and pathogenesis of proteinopathies in CTE.
神经创伤，尤其是重复性神经创伤，与渐进性神经退行性病变的发展有关，最终导致慢性创伤性脑病（CTE）。在体育运动和服兵役期间经常会受到神经创伤，通常不需要医疗护理。然而，严重和/或反复的亚临床神经创伤已被证明会造成身体和心理残疾，导致预期寿命缩短。蛋白质的错误折叠或蛋白质病是 CTE 的病理特征，其中慢性损伤导致局部和弥漫性蛋白质聚集。这些聚集体是许多神经退行性疾病（如 CTE、阿尔茨海默病、帕金森病）的重叠特征。神经创伤也是诱发这些疾病的一个重要风险因素，但这种关联的内在机制尚不十分清楚。虽然磷酸化 tau 聚合体是 CTE 的主要特征，但淀粉样蛋白-β、跨反应 DNA 结合蛋白 43（TDP-43）和α-突触核蛋白（αSyn）也是有据可查的。这些蛋白质的异常错误折叠已被证明会破坏大脑的稳态，从而导致神经退行性病变。在 CTE 中，蛋白质病变与相关神经退行性变之间的相互作用是当前研究的一个领域。在此，我们将提供有关 CTE 中蛋白病的患病率、特征和发病机制的最新文献。
{"title":"Proteinopathies and Neurotrauma: Update on Degenerative Cascades.","authors":"Stephan Quintin, Zachary A Sorrentino, Yusuf Mehkri, Sai Sriram, Sydney Weisman, Caroline Grace Davidson, Grace M Lloyd, Eric Sung, John W Figg, Brandon Lucke-Wold","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Neurotrauma, especially repetitive neurotrauma, is associated with the development of progressive neurodegeneration leading to chronic traumatic encephalopathy (CTE). Exposure to neurotrauma regularly occurs during sports and military service, often not requiring medical care. However, exposure to severe and/or repeated sub-clinical neurotrauma has been shown cause physical and psychological disability, leading to reduce life expectancy. Misfolding of proteins, or proteinopathy, is a pathological hallmark of CTE, in which chronic injury leads to local and diffuse protein aggregates. These aggregates are an overlapping feature of many neurodegenerative diseases such as CTE, Alzheimer's Disease, Parkinsons disease. Neurotrauma is also a significant risk factor for the development of these diseases, however the mechanism's underlying this association are not well understood. While phosphorylated tau aggregates are the primary feature of CTE, amyloid-beta, Transactive response DNA-binding protein 43 (TDP-43), and alpha-synuclein (αSyn) are also well documented. Aberrant misfolding of these proteins has been shown to disrupt brain homeostasis leading to neurodegeneration in a disease dependent manor. In CTE, the interaction between proteinopathies and their associated neurodegeneration is a current area of study. Here we provide an update on current literature surrounding the prevalence, characteristics, and pathogenesis of proteinopathies in CTE.</p>","PeriodicalId":92091,"journal":{"name":"JSM neurosurgery and spine","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35346375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ditte Gry Ellman, Hans Gram Novrup, Louise Helskov Jørgensen, Minna Christiansen Lund, Minna Yli-Karjanmaa, Pernille Marie Madsen, Jonas Heinrich Vienhues, Safinaz Dursun, John R Bethea, Karin Lykke-Hartmann, Roberta Brambilla, Kate Lykke Lambertsen
Nuclear factor-kappa B (NF-κB) is a key modulator of inflammation and secondary injury responses in neurodegenerative disease, including spinal cord injury (SCI). Inhibition of astroglial NF-κB reduces inflammation, enhances oligodendrogenesis and improves functional recovery after SCI, however the contribution of neuronal NF-κB to secondary inflammatory responses following SCI has yet to be investigated. We demonstrate that conditional ablation of IKK2 in Synapsin 1-expressing neurons in mice (Syn1creIKK2fl/fl) reduces activation of the classical NF-κB signaling pathway, resulting in impaired motor function and altered memory retention under naïve conditions. Following induction of a moderate SCI phosphorylated NF-κB levels decreased in the spinal cord of Syn1creIKK2fl/fl mice compared to controls, resulting in improvement in functional recovery. Histologically, Syn1creIKK2fl/fl mice exhibited reduced lesion volume but comparable microglial/leukocyte responses after SCI. In parallel, interleukin (IL)-1β expression was significantly decreased within the lesioned spinal cord, whereas IL-5, IL-6, IL-10, tumor necrosis factor (TNF) and chemokine (C-X-C motif) ligand 1 were unchanged compared to control mice. We conclude that conditional ablation of IKK2 in neurons, resulting in reduced neuronal NF-B signaling, and lead to protective effects after SCI and propose the neuronal classical NF-κB pathway as a potential target for the development of new therapeutic, neuroprotective strategies for SCI.
{"title":"Neuronal Ablation of IKK2 Decreases Lesion Size and Improves Functional Outcome after Spinal Cord Injury in Mice.","authors":"Ditte Gry Ellman, Hans Gram Novrup, Louise Helskov Jørgensen, Minna Christiansen Lund, Minna Yli-Karjanmaa, Pernille Marie Madsen, Jonas Heinrich Vienhues, Safinaz Dursun, John R Bethea, Karin Lykke-Hartmann, Roberta Brambilla, Kate Lykke Lambertsen","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Nuclear factor-kappa B (NF-κB) is a key modulator of inflammation and secondary injury responses in neurodegenerative disease, including spinal cord injury (SCI). Inhibition of astroglial NF-κB reduces inflammation, enhances oligodendrogenesis and improves functional recovery after SCI, however the contribution of neuronal NF-κB to secondary inflammatory responses following SCI has yet to be investigated. We demonstrate that conditional ablation of IKK2 in Synapsin 1-expressing neurons in mice (Syn1creIKK2<sup>fl/fl</sup>) reduces activation of the classical NF-κB signaling pathway, resulting in impaired motor function and altered memory retention under naïve conditions. Following induction of a moderate SCI phosphorylated NF-κB levels decreased in the spinal cord of Syn1creIKK2<sup>fl/fl</sup> mice compared to controls, resulting in improvement in functional recovery. Histologically, Syn1creIKK2<sup>fl/fl</sup> mice exhibited reduced lesion volume but comparable microglial/leukocyte responses after SCI. In parallel, interleukin (IL)-1β expression was significantly decreased within the lesioned spinal cord, whereas IL-5, IL-6, IL-10, tumor necrosis factor (TNF) and chemokine (C-X-C motif) ligand 1 were unchanged compared to control mice. We conclude that conditional ablation of IKK2 in neurons, resulting in reduced neuronal NF-B signaling, and lead to protective effects after SCI and propose the neuronal classical NF-κB pathway as a potential target for the development of new therapeutic, neuroprotective strategies for SCI.</p>","PeriodicalId":92091,"journal":{"name":"JSM neurosurgery and spine","volume":"5 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6051723/pdf/nihms926632.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36334959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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