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• W2987665465 abstract "Accumulation of abnormal Tau is a characteristic feature of a number of neurodegenerative disorders, called tauopathies. What is the reason for Tau toxicity in neuronal cells? In this issue of Neuron, Sohn et al., 2019Sohn P.D. Huang C.T.-L. Yan R. Fan L. Tracy T.E. Camargo C.M. Montgomery K.M. Arhar T. Mok S.-A. Freilich R. et al.Pathogenic Tau Impairs Axon Initial Segment Plasticity and Excitability Homeostasis.Neuron. 2019; 104 (this issue): 458-470Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar found that FTD mutant Tau-V337M blocks axon initial segment (AIS) plasticity, causing neuronal hyperexcitability. Accumulation of abnormal Tau is a characteristic feature of a number of neurodegenerative disorders, called tauopathies. What is the reason for Tau toxicity in neuronal cells? In this issue of Neuron, Sohn et al., 2019Sohn P.D. Huang C.T.-L. Yan R. Fan L. Tracy T.E. Camargo C.M. Montgomery K.M. Arhar T. Mok S.-A. Freilich R. et al.Pathogenic Tau Impairs Axon Initial Segment Plasticity and Excitability Homeostasis.Neuron. 2019; 104 (this issue): 458-470Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar found that FTD mutant Tau-V337M blocks axon initial segment (AIS) plasticity, causing neuronal hyperexcitability. Tau protein was discovered as one of the first microtubule-associated proteins (MAPs). Tau is mainly enriched in the axons of neurons with a primary function to promote axonal microtubule assembly and stability. In brains of Alzheimer’s disease (AD) patients, Tau is subject to numerous post-translational modifications, including phosphorylation, acetylation, and O-GlcNAcylation. Hyperphosphorylation of Tau decreases its binding affinity to microtubules, can result in mislocalization of Tau to the soma and dendrites, and is thought to promote neurofibrillary tangle (NFT) formation, one of the main histopathological hallmarks of AD (Wang and Mandelkow, 2016Wang Y. Mandelkow E. Tau in physiology and pathology.Nat. Rev. Neurosci. 2016; 17: 5-21Crossref PubMed Scopus (314) Google Scholar). Recent cryo-EM structures of Tau fibrils derived from brains of AD patients have provided exciting new insight into abnormal filament structures at the atomic level (Fitzpatrick et al., 2017Fitzpatrick A.W.P. Falcon B. He S. Murzin A.G. Murshudov G. Garringer H.J. Crowther R.A. Ghetti B. Goedert M. Scheres S.H.W. Cryo-EM structures of tau filaments from Alzheimer’s disease.Nature. 2017; 547: 185-190Crossref PubMed Scopus (1026) Google Scholar). Intracellular Tau inclusions are not restricted to AD and are found in several different forms of dementia, such as progressive supranuclear palsy syndrome (PSPS), Chronic traumatic encephalopathy (CTE), and Frontotemporal Dementia (FTD), collectively known as tauopathies. Tau protein is encoded by the MAPT gene and to date more than 50 pathogenic mutations have been described resulting in a spectrum of tauopathies. MAPT mutations account for 5%–10% of the familial cases with typical FTD. The mutations are mainly clustered from exon 9 to 13, encoding the four microtubule binding domains in Tau, and show their effects through a toxic gain-of-function mechanism or loss-of-function conditions (Rossi and Tagliavini, 2015Rossi G. Tagliavini F. Frontotemporal lobar degeneration: old knowledge and new insight into the pathogenetic mechanisms of tau mutations.Front. Aging Neurosci. 2015; 7: 192Crossref PubMed Scopus (31) Google Scholar). The pathogenic mutations exhibit differing properties in terms of microtubule-binding affinity, microtubule bundling, and microtubule dynamics. Other mutations have been shown to promote aggregation, alter organelle function, and/or impair axonal transport (Figure 1). Although FTD-Tau presentations are relatively homogeneous in the disease course, various pathogenic Tau mutations result in diverging clinical phenotypes. For example, in addition to the typical behavior and language dysfunctions, some FTD patients have altered neuronal excitability and seizures (Beagle et al., 2017Beagle A.J. Darwish S.M. Ranasinghe K.G. La A.L. Karageorgiou E. Vossel K.A. Relative incidence of seizures and myoclonus in Alzheimer’s disease, dementia with lewy bodies, and frontotemporal dementia.J. Alzheimers Dis. 2017; 60: 211-223Crossref PubMed Scopus (70) Google Scholar). However, the underlying cell biology leading to excitability defects is not fully understood. In a series of well-controlled experiments, Sohn et al., 2019Sohn P.D. Huang C.T.-L. Yan R. Fan L. Tracy T.E. Camargo C.M. Montgomery K.M. Arhar T. Mok S.-A. Freilich R. et al.Pathogenic Tau Impairs Axon Initial Segment Plasticity and Excitability Homeostasis.Neuron. 2019; 104 (this issue): 458-470Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar in this issue of Neuron provide new mechanistic insight into how a specific Tau mutation can lead to excess activity in neural networks. The researchers found that iPSC-derived neurons from FTD patients carrying a Tau-V337M mutation have a shorter axon initial segment (AIS), which is a specialized structure at the base of the axon that generates and shapes the action potential before it is propagated along the axon. The AIS did not respond to chronic depolarization, suggesting that the plasticity of the AIS in FTD-patient-derived neurons was impaired. Activity-dependent AIS plasticity has been shown in several model systems and neuronal cell types (Evans et al., 2015Evans M.D. Dumitrescu A.S. Kruijssen D.L.H. Taylor S.E. Grubb M.S. Rapid Modulation of Axon Initial Segment Length Influences Repetitive Spike Firing.Cell Rep. 2015; 13: 1233-1245Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). The finding by Sohn et al. provides the first evidence that chronic depolarization shortens the AIS of human excitatory neurons. The authors used an impressive number of independent isogenic controls to exclude the possibility that the observed effect is due to clonal variability or genetic background differences between the wild-type and Tau-V337M neurons. For instance, the Tau-V337M mutation was corrected in FTD patient neurons and newly introduced into wild-type iPSC clones using CRISPR-Cas9. The other strength of the approach is that the iPSC model does not rely on overexpression of the mutant Tau protein. This study is a prime example of the emerging potential of human cellular model systems and genome editing tools to study the link between disease mutations, pathophysiological alterations, and neurodegeneration (Penney et al., 2019Penney J. Ralvenius W.T. Tsai L.-H. Modeling Alzheimer’s disease with iPSC-derived brain cells.Mol. Psychiatry. 2019; https://doi.org/10.1038/s41380-019-0468-3Crossref Scopus (153) Google Scholar). Does the observed AIS plasticity phenotype lead to abnormal neuronal excitability in neurons bearing the mutation? To answer that specific question Sohn et al. measured the electrophysiological properties of control and Tau mutant neurons using multi-electrode arrays before and after depolarization. Notably, the firing rate after depolarization was markedly increased in Tau-V337M neurons. Together the findings showed that the AIS plasticity phenotype in patient-derived neurons correlates with impaired homeostatic control in response to depolarization. To determine how the mutant Tau interferes with AIS plasticity and neuronal excitability, Sohn and colleagues focused on the possibility that the V337M mutation alters the binding affinity of Tau with components of the AIS cytoskeleton. A previous study suggested that Tau interacts with the microtubule plus-end tracking end-binding protein 3 (EB3), whose localization is enriched at the AIS (Sayas et al., 2015Sayas C.L. Tortosa E. Bollati F. Ramírez-Ríos S. Arnal I. Avila J. Tau regulates the localization and function of End-binding proteins 1 and 3 in developing neuronal cells.J. Neurochem. 2015; 133: 653-667Crossref PubMed Scopus (54) Google Scholar). The authors map three potential binding sites of Tau to EB3—one of them close to the V337M mutation—and show that Tau-V337M has stronger affinity to EB3 than the wild-type Tau does. Since EB3 has been shown to interact with and stabilize the major AIS component Ankyrin G (AnkG) (Fréal et al., 2016Fréal A. Fassier C. Le Bras B. Bullier E. De Gois S. Hazan J. Hoogenraad C.C. Couraud F. Cooperative Interactions between 480 kDa Ankyrin-G and EB proteins assemble the axon initial segment.J. Neurosci. 2016; 36: 4421-4433Crossref PubMed Scopus (45) Google Scholar), the authors hypothesized that this increased binding of the mutant Tau may lead to higher EB3 levels at the AIS. Higher EB3 levels may cause a subsequent increase in AnkG stability, which could make the patient neurons unresponsive to depolarization. Consistent with this model are the data that colocalization of Tau, EB3, and AnkG is more prominent at AIS in Tau-V337M neurons. Depleting EB3 or Tau in these neurons restored AnkG length and the ability of the AIS to react to chronic depolarization, while overexpressing EB3 in control neurons led to a blockage in AIS plasticity, similar to what is seen in the mutant Tau-V337M neurons. One of the remaining questions is how changes in cytoskeletal proteins may lead to altered AIS plasticity. The authors suggest that the elongated AIS may increase localization of Ca2+ channels, activate local downstream Ca2+ effectors, and further promote AIS plasticity (Evans et al., 2015Evans M.D. Dumitrescu A.S. Kruijssen D.L.H. Taylor S.E. Grubb M.S. Rapid Modulation of Axon Initial Segment Length Influences Repetitive Spike Firing.Cell Rep. 2015; 13: 1233-1245Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). The excess of EB3 at the AIS may somehow disturb calcium signaling and prevent AIS plasticity modulation. On the other hand, an increase in AnkG stability caused by its increased binding to EB3 along the microtubule lattice may increase the stiffness of the AIS, preventing it from further remodeling (Fréal et al., 2016Fréal A. Fassier C. Le Bras B. Bullier E. De Gois S. Hazan J. Hoogenraad C.C. Couraud F. Cooperative Interactions between 480 kDa Ankyrin-G and EB proteins assemble the axon initial segment.J. Neurosci. 2016; 36: 4421-4433Crossref PubMed Scopus (45) Google Scholar). However, how exactly Tau-V337M and EB3 cooperates with the other AIS components to hinder AIS remodeling is currently poorly understood. Future live cell imaging and photobleaching experiments should reveal whether AnkG turnover at the AIS is altered in Tau-V337M neurons. In a way AIS plasticity can be viewed as a dynamic (dis)assembly process during the early stage of neuronal development involving several AIS membrane, scaffolding, and cytoskeletal proteins (Fréal et al., 2019Fréal A. Rai D. Tas R.P. Pan X. Katrukha E.A. van de Willige D. Stucchi R. Aher A. Yang C. Altelaar A.F.M. et al.Feedback-Driven Assembly of the Axon Initial Segment.Neuron. 2019; (S0896-6273(19)30655-5)https://doi.org/10.1016/j.neuron.2019.07.029Abstract Full Text Full Text PDF Scopus (29) Google Scholar). This study also triggers a much broader discussion about potential future therapeutic intervention in FTD-Tau and other tauopathies. The picture that emerges suggests that not all disease-causing mutations in Tau work in a similar manner. Tau mutants can perturbate many different neuronal functions, including microtubule dynamics, organelle function, and axonal trafficking as well as AIS plasticity (Figure 1). This may point to a clinical sub-classification of Tau-related disorders. Additional studies to systematically characterize the specific cellular mechanisms underlying each Tau mutation individually may lead to new approaches for future therapeutic intervention. It is possible to envision a future model in which patients are assessed for their genetic risk and then stratified into clinical subgroups based on specific (combination) therapies that reflect their underlying Tau disease pathogenesis and human biology. Sohn and colleagues have provided the first steps in this direction by answering important biological questions regarding Tau toxicity in appropriate human cell models. The authors are employees of Genentech, Inc., a member of the Roche group. The authors declare that they have no additional conflicts of interest. Pathogenic Tau Impairs Axon Initial Segment Plasticity and Excitability HomeostasisSohn et al.NeuronSeptember 18, 2019In BriefFrontotemporal dementia (FTD) with tau pathology is associated with aberrant hyperexcitability of neuronal networks. In human iPSC-derived neurons, Sohn et al. demonstrates that FTD-causing tau mutation abolishes activity-dependent plasticity of the axon initial segment and impairs homeostasis of neuronal activity via impacting AIS cytoskeleton, resulting in dysregulation of neuronal network function. Full-Text PDF Open Archive" @default.
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• W2987665465 title "Solving the Mysteries of Dementia: FTD Mutant Tau Impairs Structural Axon Initial Segment Plasticity" @default.
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