دورية أكاديمية
Frontotemporal Lobar Dementia Mutant Tau Impairs Axonal Transport through a Protein Phosphatase 1γ-Dependent Mechanism.
| العنوان: | Frontotemporal Lobar Dementia Mutant Tau Impairs Axonal Transport through a Protein Phosphatase 1γ-Dependent Mechanism. |
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| المؤلفون: | Combs B; Department of Translational Neuroscience, Michigan State University, Grand Rapids, Michigan 49503 combsben@msu.edu nkanaan@msu.edu., Christensen KR; Department of Translational Neuroscience, Michigan State University, Grand Rapids, Michigan 49503.; Neuroscience Program, Michigan State University, East Lansing, Michigan 48824., Richards C; Department of Translational Neuroscience, Michigan State University, Grand Rapids, Michigan 49503., Kneynsberg A; Department of Translational Neuroscience, Michigan State University, Grand Rapids, Michigan 49503.; Neuroscience Program, Michigan State University, East Lansing, Michigan 48824., Mueller RL; Department of Translational Neuroscience, Michigan State University, Grand Rapids, Michigan 49503.; Neuroscience Program, Michigan State University, East Lansing, Michigan 48824., Morris SL; Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, Illinois 60612., Morfini GA; Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, Illinois 60612.; Marine Biological Laboratory, Woods Hole, Massachusetts 02543., Brady ST; Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, Illinois 60612.; Marine Biological Laboratory, Woods Hole, Massachusetts 02543., Kanaan NM; Department of Translational Neuroscience, Michigan State University, Grand Rapids, Michigan 49503 combsben@msu.edu nkanaan@msu.edu.; Neuroscience Program, Michigan State University, East Lansing, Michigan 48824.; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, Michigan 49503. |
| المصدر: | The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2021 Nov 10; Vol. 41 (45), pp. 9431-9451. Date of Electronic Publication: 2021 Oct 04. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: Society for Neuroscience Country of Publication: United States NLM ID: 8102140 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1529-2401 (Electronic) Linking ISSN: 02706474 NLM ISO Abbreviation: J Neurosci Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Washington, DC : Society for Neuroscience Original Publication: [Baltimore, Md.] : The Society, c1981- |
| مواضيع طبية MeSH: | Frontotemporal Dementia*, Axonal Transport/*drug effects , Neurons/*metabolism , Protein Phosphatase 1/*metabolism , tau Proteins/*pharmacology, Animals ; Cells, Cultured ; Decapodiformes ; Female ; Hippocampus ; Humans ; Male ; Mutation ; Neurons/drug effects ; Rats ; tau Proteins/genetics |
| مستخلص: | Pathologic tau modifications are characteristic of Alzheimer's disease and related dementias, but mechanisms of tau toxicity continue to be debated. Inherited mutations in tau cause early onset frontotemporal lobar dementias (FTLD-tau) and are commonly used to model mechanisms of tau toxicity in tauopathies. Previous work in the isolated squid axoplasm model demonstrated that several pathogenic forms of tau inhibit axonal transport through a mechanism involving activation of protein phosphatase 1 (PP1). Here, we determined that P301L and R5L FTLD mutant tau proteins elicit a toxic effect on axonal transport as monomeric proteins. We evaluated interactions of wild-type or mutant tau with specific PP1 isoforms (α, β, and γ) to examine how the interaction contributes to this toxic effect using primary rat hippocampal neurons from both sexes. Pull-down and bioluminescence resonance energy transfer experiments revealed selective interactions of wild-type tau with PP1α and PP1γ isoforms, but not PP1β, which were significantly increased by the P301L tau mutation. The results from proximity ligation assays confirmed the interaction in primary hippocampal neurons. Moreover, expression of FTLD-linked mutant tau in these neurons enhanced levels of active PP1, also increasing the pausing frequency of fluorescently labeled vesicles in both anterograde and retrograde directions. Knockdown of PP1γ, but not PP1α, rescued the cargo-pausing effects of P301L and R5L tau, a result replicated by deleting a phosphatase-activating domain in the amino terminus of P301L tau. These findings support a model of tau toxicity involving aberrant activation of a specific PP1γ-dependent pathway that disrupts axonal transport in neurons. SIGNIFICANCE STATEMENT Tau pathology is closely associated with neurodegeneration in Alzheimer's disease and other tauopathies, but the toxic mechanisms remain a debated topic. We previously proposed that pathologic tau forms induce dysfunction and degeneration through aberrant activation of a PP1-dependent pathway that disrupts axonal transport. Here, we show that tau directly interacts with specific PP1 isoforms, increasing levels of active PP1. Pathogenic tau mutations enhance this interaction, further increasing active PP1 levels and impairing axonal transport in isolated squid axoplasm and primary hippocampal neurons. Mutant-tau-mediated impairment of axonal transport was mediated by PP1γ and a phosphatase-activating domain located at the amino terminus of tau. This work has important implications for understanding and potentially mitigating tau-mediated neurotoxicity in tauopathies. (Copyright © 2021 Combs et al.) |
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| معلومات مُعتمدة: | R21 NS120126 United States NS NINDS NIH HHS; R01 NS082730 United States NS NINDS NIH HHS; R01 NS118177 United States NS NINDS NIH HHS; P30 AG053760 United States AG NIA NIH HHS; R01 AG044372 United States AG NIA NIH HHS; R01 AG067762 United States AG NIA NIH HHS; P30 AG072931 United States AG NIA NIH HHS |
| فهرسة مساهمة: | Keywords: Alzheimer's disease; axonal transport; neurodegeneration; protein phosphatase 1; tau protein; tauopathies |
| المشرفين على المادة: | 0 (tau Proteins) EC 3.1.3.16 (Protein Phosphatase 1) |
| تواريخ الأحداث: | Date Created: 20211005 Date Completed: 20211230 Latest Revision: 20220415 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC8580143 |
| DOI: | 10.1523/JNEUROSCI.1914-20.2021 |
| PMID: | 34607969 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1529-2401 |
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| DOI: | 10.1523/JNEUROSCI.1914-20.2021 |