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Effects of P301L-TAU on post-translational modifications of microtubules in human iPSC-derived cortical neurons and TAU transgenic mice

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Neural Regeneration Research 2025年第8期20卷 2348-2360页

作者： mohamed aghyad al kabbani Christoph Köhler Hans Zempel Institute of Human Genetics Faculty of Medicine and University Hospital CologneUniversity of CologneCologneGermany Center for Molecular Medicine Cologne(CMMC) University of CologneCologneGermany Center Anatomy Department ⅡMedical FacultyUniversity of CologneCologneGermany

TAU is a microtubule-associated protein that promotes microtubule assembly and stability in the *** is missorted and aggregated in an array of diseases known as *** are essential for neuronal function and regulated via a complex set of post-translational modifications,changes of which affect microtubule stability and dynamics,microtubule interaction with other proteins and cellular structures,and mediate recruitment of microtubule-severing *** impairment of microtubule dynamics causes neuronal dysfunction,we hypothesize cognitive impairment in human disease to be impacted by impairment of microtubule *** therefore aimed to study the effects of a disease-causing mutation of TAU(P301L)on the levels and localization of microtubule post-translational modifications indicative of microtubule stability and dynamics,to assess whether P301L-TAU causes stability-changing modifications to *** investigate TAU localization,phosphorylation,and effects on tubulin post-translational modifications,we expressed wild-type or P301L-TAU in human MAPT-KO induced pluripotent stem cell-derived neurons(i Neurons)and studied TAU in neurons in the hippocampus of mice transgenic for human P301L-TAU(p R5 mice).Human neurons expressing the longest TAU isoform(2N4R)with the P301L mutation showed increased TAU phosphorylation at the AT8,but not the p-Ser-262 epitope,and increased polyglutamylation and acetylation of microtubules compared with endogenous TAU-expressing neurons.P301L-TAU showed pronounced somatodendritic presence,but also successful axonal enrichment and a similar axodendritic distribution comparable to exogenously expressed 2N4R-wildtype-TAU.P301L-TAU-expressing hippocampal neurons in transgenic mice showed prominent missorting and tauopathy-typical AT8-phosphorylation of TAU and increased polyglutamylation,but reduced acetylation,of microtubules compared with non-transgenic *** sum,P301L-TAU results in changes in micr

关键词： human induced pluripotent stem cell microtubules P301L pR5 mice TAU tauopathy tubulin code

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AAV-based gene therapy approaches for genetic forms of tauopathies and related neurogenetic disorders

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BIOCELL 2022年第4期46卷 847-853页

作者： mohamed aghyad al kabbani GILBERT WUNDERLICH CHRISTOPH KÖHLER HANS ZEMPEL Faculty of Medicine and University Hospital Cologne Institute of Human GeneticsUniversity of CologneCologne50931Germany Faculty of Medicine and University Hospital Cologne Center for Molecular Medicine Cologne(CMMC)University of CologneCologne50931Germany Faculty of Medicine and University Hospital Cologne Department of NeurologyUniversity of CologneCologne50937Germany Faculty of Medicine and University Hospital Cologne Center for Rare DiseasesUniversity of CologneCologne50937Germany Faculty of Medicine and University Hospital Cologne Center AnatomyDepartment of Molecular and Translational NeuroscienceUniversity of CologneCologne50931Germany

Tauopathies comprise a spectrum of genetic and sporadic neurodegenerative diseases mainly characterized by the presence of hyperphosphorylated TAU protein aggregations in neurons or *** therapy,in particular adeno-associated virus(AAV)-based,is an effective medical approach for difficult-to-treat genetic diseases for which there are no convincing traditional therapies,such as *** AAV-based gene therapy to treat,in particular,genetic tauopathies has many potential therapeutic benefits,but also drawbacks which need to be addressed in order to successfully and efficiently adapt this still unconventional therapy for the various types of *** this Viewpoint,we briefly introduce some potentially treatable tauopathies,classify them according to their etiology,and discuss the potential advantages and possible problems of AAV-based gene ***,we outline a future vision for the application of this promising therapeutic approach for genetic and sporadic tauopathies.

关键词： Tauopathies Neurogenetic diseases AAV-based gene therapy Neurodegeneration alzheimer disease TAU

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