دورية أكاديمية
Serpin neuropathology in the P497S UBQLN2 mouse model of ALS/FTD.
العنوان: | Serpin neuropathology in the P497S UBQLN2 mouse model of ALS/FTD. |
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المؤلفون: | Higgins NR; Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.; Center for Biomedical Engineering and Technology, Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA., Greenslade JE; Center for Biomedical Engineering and Technology, Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA., Wu JJ; Center for Biomedical Engineering and Technology, Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA., Miranda E; Department of Biology and Biotechnologies 'Charles Darwin', Pasteur Institute - Cenci Bolognetti Foundation, Sapienza University of Rome, Rome, Italy., Galliciotti G; Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Monteiro MJ; Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.; Center for Biomedical Engineering and Technology, Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA. |
المصدر: | Brain pathology (Zurich, Switzerland) [Brain Pathol] 2021 Sep; Vol. 31 (5), pp. e12948. Date of Electronic Publication: 2021 Mar 29. |
نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: International Society of Neuropathology Country of Publication: Switzerland NLM ID: 9216781 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1750-3639 (Electronic) Linking ISSN: 10156305 NLM ISO Abbreviation: Brain Pathol Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: Zürich, Switzerland : International Society of Neuropathology, [1990- |
مواضيع طبية MeSH: | Adaptor Proteins, Signal Transducing/*metabolism , Amyotrophic Lateral Sclerosis/*genetics , Amyotrophic Lateral Sclerosis/*pathology , Autophagy-Related Proteins/*metabolism , Frontotemporal Dementia/*pathology , Serpins/*genetics, Adaptor Proteins, Signal Transducing/genetics ; Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Autophagy-Related Proteins/genetics ; Disease Models, Animal ; Frontotemporal Dementia/genetics ; Frontotemporal Dementia/metabolism ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Neurons/metabolism ; Motor Neurons/pathology ; Serpins/metabolism ; Spinal Cord/pathology ; Mice |
مستخلص: | Accumulating evidence suggests X-linked dominant mutations in UBQLN2 cause amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD) through both loss- and gain-of-function mechanisms. However, the mechanisms by which the mutations cause disease are still unclear. The goal of the study was to uncover the possible pathomechanism(s) by which UBQLN2 mutations cause ALS/FTD. An analysis of proteomic changes in neuronal tissue was used to identify proteins with altered accumulation in the P497S UBQLN2 transgenic mouse model of ALS/FTD. We then used immunocytochemistry and biochemical techniques to confirm protein changes in the mutant P497S mice. Additionally, we used cell lines inactivated of UBQLN2 expression to determine whether its loss underlies the alteration in the proteins seen in P497S mice. The proteome screen identified a dramatic alteration of serine protease inhibitor (serpin) proteins in the mutant P497S animals. Double immunofluorescent staining of brain and spinal cord tissues of the mutant and control mice revealed an age-dependent change in accumulation of Serpin A1, C1, and I1 in puncta whose staining colocalized with UBQLN2 puncta in the mutant P497S mice. Serpin A1 aggregation in P497S animals was confirmed by biochemical extraction and filter retardation assays. A similar phenomenon of serpin protein aggregation was found in HeLa and NSC34 motor neuron cells with inactivated UBQLN2 expression. We found aberrant aggregation of serpin proteins, particularly Serpin A1, in the brain and spinal cord of the P497S UBQLN2 mouse model of ALS/FTD. Similar aggregation of serpin proteins was found in UBQLN2 knockout cells suggesting that serpin aggregation in the mutant P497S animals may stem from loss of UBQLN2 function. Because serpin aggregation is known to cause disease through both loss- and gain-of-function mechanisms, we speculate that their accumulation in the P497S mouse model of ALS/FTD may contribute to disease pathogenesis through similar mechanism(s). (© 2021 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.) |
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معلومات مُعتمدة: | R01 NS098243 United States NS NINDS NIH HHS; R01 NS100008 United States NS NINDS NIH HHS; RF1 NS098243 United States NS NINDS NIH HHS |
فهرسة مساهمة: | Keywords: Ubiquilin-2 (UBQLN2); amyotrophic lateral sclerosis (ALS); frontotemporal dementia (FTD); protein aggregation; serpin |
المشرفين على المادة: | 0 (Adaptor Proteins, Signal Transducing) 0 (Autophagy-Related Proteins) 0 (Serpins) 0 (UBQLN2 protein, mouse) |
SCR Disease Name: | Frontotemporal Dementia With Motor Neuron Disease |
تواريخ الأحداث: | Date Created: 20210329 Date Completed: 20220203 Latest Revision: 20240226 |
رمز التحديث: | 20240226 |
مُعرف محوري في PubMed: | PMC8387369 |
DOI: | 10.1111/bpa.12948 |
PMID: | 33780087 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1750-3639 |
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DOI: | 10.1111/bpa.12948 |