The Role of Tau Proteoforms in Health and Disease

Molecular Neurobiology, Journal Year: 2023, Volume and Issue: 60(9), P. 5155 - 5166

Published: June 2, 2023

Language: Английский

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Big Tau: What We Know, and We Need to Know

eNeuro, Journal Year: 2023, Volume and Issue: 10(5), P. ENEURO.0052 - 23.2023

Published: May 1, 2023

Tau is a microtubule-associated protein (MAP) that has multiple isoforms generated by alternative splicing of the MAPT gene at range 45–60 kDa [low-molecular-weight (LMW) tau] as well unique isoform termed Big tau containing an additional exon 4a encoding large projecting domain ∼250 aa to form 110 kDa. expressed in adult PNS neurons such DRG and specific regions CNS cerebellum developmental transition from LMW during postnatal period. Despite conserved size exons across vertebrate phylogeny, there no sequence homology among different species outside Mammalia class, which underscores focus on structural preservation tau. original discovery early 1990s, been little progress elucidating its physiological properties pathologic implications. We propose may be able improve axonal transport axons speculate potential protective preventing aggregation conditions. This perspective highlights importance benefits understanding role neuronal health disease.

Language: Английский

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Regulation of Tau Expression in Superior Cervical Ganglion (SCG) Neurons In Vivo and In Vitro

Cells, Journal Year: 2023, Volume and Issue: 12(2), P. 226 - 226

Published: Jan. 5, 2023

The superior cervical ganglion (SCG) is part of the autonomic nervous system providing sympathetic innervation to head and neck, has been regularly used prepare postnatal neuronal cultures for cell biological studies. We found that during development these neurons change tau expression from low molecular weight (LMW) isoforms Big tau, with potential affect functions associated such as microtubule dynamic axonal transport. contains large 4a exon transforms LMW 45–60 kDa 110 kDa. describe reporting transition which started at late embryonic stages completed by about 4–5 weeks postnatally. confirmed presence in dissociated SCG making them an ideal study function neurons. explants examine response lesion returned gradually along regrowing neurites suggesting it does not drives regeneration, but facilitates structure/function mature structural/functional roles remain unknown, intriguing express appear less vulnerable tauopathies.

Language: Английский

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The unique properties of Big tau in the visual system

Cytoskeleton, Journal Year: 2024, Volume and Issue: 81(9-10), P. 488 - 499

Published: May 18, 2024

Tau is a microtubule associated protein that plays important roles in regulating the properties of microtubules and axonal transport, as well tauopathies with toxic aggregates leading to neurodegenerative diseases. It encoded by MAPT gene forming multiple isoforms (45-60 kDa) alternative splicing which are developmentally regulated. The high molecular weight (MW) tau isoform 105 kDa, termed Big tau, was originally discovered peripheral nervous system (PNS) but later found selective CNS areas. contains an additional large exon 4a generating long projecting domain about 250 amino acids. Here we investigated visual rats, its distribution retinal ganglion cells optic nerve developmental regulation using biochemical, histological analyses. We expresses 95 kDa (termed middle MW) containing exons 4a, 6 10 defines 4 microtubule-binding repeats (4R). lacks 2/3 shares extensive phosphorylation characteristic other isoforms. Importantly, early development only low MW (3R) switching both (4R) adult neurons their corresponding axons. This unique structure expression pattern hypothesize specific different from what has been previously described PNS areas system.

Language: Английский

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Development of MAPT S305 mutation human iPSC lines exhibiting elevated 4R tau expression and functional alterations in neurons and astrocytes

Cell Reports, Journal Year: 2024, Volume and Issue: 43(12), P. 115013 - 115013

Published: Nov. 27, 2024

Language: Английский

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Big tau: What, how, where and why

Cytoskeleton, Journal Year: 2023, Volume and Issue: 81(1), P. 10 - 15

Published: Aug. 14, 2023

Abstract Over the last 50 years different isoforms of tau proteins (45–60 kDa) have been a focus research because their roles in modulating dynamic properties microtubules shaping structure and function neurons but also becoming center attention pathology neurodegeneration associated with tauopathies. Much less has given to Big tau, unique isoform containing exon 4a encoding about 250 amino acids form much longer projection domain protein 110 kDa. is expressed peripheral selective regions central nervous system defined transition during postnatal developmental stages. Although was discovered 30 ago, there persistent gap knowledge regarding its physiological pathological implications. This Perspective summarizes progress so far defining expression within outside system, proposes role for improving axonal transport projecting axons, considers potential averting aggregation tauopathies highlights need further progress.

Language: Английский

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Tau here, tau there, tau almost everywhere: Clarifying the distribution of tau in the adult CNS

Cytoskeleton, Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 16, 2023

Abstract The microtubule‐associated protein tau has gained significant attention over the last several decades primarily due to its apparent role in pathogenesis of diseases, most notably Alzheimer's disease. While field focused largely on tau's potential contributions disease mechanisms, comparably less work normal physiology. Moreover, as grown, some misconceptions and dogmas regarding physiology have become engrained traditional narrative. Here, one common tau, namely cellular/subcellular distribution CNS, is discussed. literature describing presence neuronal somata, dendrites, axons synapses, well glial cells described. origins for erroneous description an “axon‐specific,” “axon‐enriched” and/or “neuron‐specific” are discussed well. goal this help address these specific dogmatic provide a concise localization adult CNS. This information can refine our collective understanding of‐ hypotheses about biology pathobiology.

Language: Английский

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Development of Mapt S305 Mutation Models Exhibiting Elevated 4r Tau Expression, Resulting in Altered Neuronal and Astrocytic Function

Published: Jan. 1, 2023

Due to the importance of 4R tau in pathogenicity primary tauopathies, it has been challenging model these diseases iPSC-derived neurons, which express very low levels tau. To address this problem we have developed a panel isogenic iPSC lines carrying MAPT splice-site mutations S305S, S305I or S305N, derived from four different donors. All three significantly increased proportion expression iPSC-neurons and astrocytes, with up 80% transcripts S305N neurons as early 4 weeks differentiation. Transcriptomic functional analyses S305 mutant revealed shared disruption glutamate signaling synaptic maturity, but divergent effects on mitochondrial bioenergetics. In iPSC-astrocytes, induced lysosomal inflammation exacerbated internalization exogenous that may be precursor glial pathologies observed many tauopathies. conclusion, present novel human unprecedented astrocytes. These recapitulate previously characterized tauopathy-relevant phenotypes, also highlight differences between wild type proteins. We will highly beneficial tauopathy researchers enabling more complete understanding pathogenic mechanisms underlying tauopathies across cell types.

Language: Английский

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The unique properties of Big tau in the visual system

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: July 12, 2023

Abstract Tau is a microtubule associated protein that plays important roles in regulating the properties of microtubules and axonal transport, as well tauopathies with toxic aggregates leading to neurodegenerative diseases. It encoded by MAPT gene forming multiple isoforms alternative splicing exons 2/3 at N-terminal exon 10 which determines numbers binding repeats (3R or 4R). The high molecular weight (MW) tau isoform termed Big contains an additional large 4a generating long projecting domain expressed 110 kDa protein. was originally discovered peripheral nervous system but later found selective CNS areas project periphery cerebellum visual system. However, there gap knowledge understanding expression patterns role during normal neuronal development pathological conditions relative common low MW isoforms. Here we investigated retina optic nerve particular its unique structure middle 90kDa distribution retinal ganglion cells axons nerve. We expresses 6 (4R), lacking sharing extensive phosphorylation characteristic other Importantly, early only (3R) switching both (4R) adult neurons their corresponding axons. This pattern likely different than what has been previously described, requiring more research elucidate detailed

Language: Английский

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