Phosphoregulation of Tau modulates inhibition of kinesin-1 motility

Stern, Jamie; Lessard, Dominique V.; Hoeprich, Gregory J.; Morfini, Gerardo; Berger, Christopher L.

doi:10.1091/mbc.e16-10-0728

Cited by 59 publications

(103 citation statements)

References 38 publications

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“…Tau is modified by a variety of post‐translational modifications, and over 85 putative phosphorylation sites have been identified . While the function of most of these sites is unknown, phosphorylation of tyrosine 18 weakens tau's affinity to microtubules and in turn the inhibition of kinesin‐1 motility . Thus, multiple layers of regulation allow the cell to tune the local density and dynamics of tau to control trafficking in specific subcellular regions …”

Section: Discussionmentioning

confidence: 99%

“…The length of the projection domain modulates tau's effect on motor protein motility, with the shortest isoform exhibiting the strongest inhibition . Over 85 putative phosphorylation sites have been identified for tau, and tau phosphorylation modulates the dynamic equilibrium between static and transient binding to the microtubule . Tau phosphorylation is tightly regulated during development and aberrant phosphorylation is linked to disease …”

Section: Introductionmentioning

confidence: 99%

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Tau directs intracellular trafficking by regulating the forces exerted by kinesin and dynein teams

Chaudhary

Berger

et al. 2017

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Organelles, proteins, and mRNA are transported bidirectionally along microtubules by plus-end directed kinesin and minus-end directed dynein motors. Microtubules are decorated by microtubule-associated proteins (MAPs) that organize the cytoskeleton, regulate microtubule dynamics and modulate the interaction between motor proteins and microtubules to direct intracellular transport. Tau is a neuronal MAP that stabilizes axonal microtubules and crosslinks them into bundles. Dysregulation of tau leads to a range of neurodegenerative diseases known as tauopathies including Alzheimer's disease (AD). Tau reduces the processivity of kinesin and dynein by acting as an obstacle on the microtubule. Single-molecule assays indicate that kinesin-1 is more strongly inhibited than kinesin-2 or dynein, suggesting tau might act to spatially modulate the activity of specific motors. To investigate the role of tau in regulating bidirectional transport, we isolated phagosomes driven by kinesin-1, kinesin-2, and dynein and reconstituted their motility along microtubules. We find that tau biases bidirectional motility towards the microtubule minus-end in a dose-dependent manner. Optical trapping measurements show that tau increases the magnitude and frequency of forces exerted by dynein through inhibiting opposing kinesin motors. Mathematical modeling indicates that tau controls the directional bias of intracellular cargoes through differentially tuning the processivity of kinesin-1, kinesin-2, and dynein. Taken together, these results demonstrate that tau modulates motility in a motor-specific manner to direct intracellular transport, and suggests that dysregulation of tau might contribute to neurodegeneration by disrupting the balance of plus- and minus-end directed transport.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Tau directs intracellular trafficking by regulating the forces exerted by kinesin and dynein teams

Chaudhary

Berger

et al. 2017

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“…Similar to other MAPs reviewed here, it has been demonstrated that tau phosphorylation reduces its affinity for microtubules or its ability to promote microtubule polymerization, resulting in overall microtubule instability (Avila et al, ). Phosphorylation at specific sites, such as Y18, regulates the dynamicity of tau on the microtubule and has significant effects on kinesin‐1 motility (Stern et al, ). Whether neuronal cell death is a consequence of microtubule instability, transport, or tau neurofibrillary tangles is controversial (Dawson et al, ).…”

Section: Introductionmentioning

confidence: 99%

ReMAPping the microtubule landscape: How phosphorylation dictates the activities of microtubule‐associated proteins

Ramkumar

Jong

Ori-McKenney

2017

Developmental Dynamics

156

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Classical microtubule-associated proteins (MAPs) were originally identified based on their co-purification with microtubules assembled from mammalian brain lysate. They have since been found to perform a range of functions involved in regulating the dynamics of the microtubule cytoskeleton. Most of these MAPs play integral roles in microtubule organization during neuronal development, microtubule remodeling during neuronal activity, and microtubule stabilization during neuronal maintenance. As a result, mutations in MAPs contribute to neurodevelopmental disorders, psychiatric conditions, and neurodegenerative diseases. MAPs are post-translationally regulated by phosphorylation depending on developmental time point and cellular context. Phosphorylation can affect the microtubule affinity, cellular localization, or overall function of a particular MAP and can thus have profound implications for neuronal health. Here we review MAP1, MAP2, MAP4, MAP6, MAP7, MAP9, tau, and DCX, and how each is regulated by phosphorylation in neuronal physiology and disease. Developmental Dynamics 247:138-155,

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“…Intriguingly, mitochondrial anterograde transport seems to be more vulnerable in AD . One possible mechanism underlying the more obvious loss of mitochondrial anterograde transport is that tau inhibits kinesin‐1 activity but has little effect on dynein‐based movement . In addition to mitochondrial anterograde motors, mitochondrial anchor protein syntaphilin buds out of axonal mitochondria and is further degraded in AD‐related mutant hAPP Tg neurons, which increases mitochondrial retrograde movements in axons (Figure A,B) .…”

Section: Implications Of Axonal Mitochondrial Transport For Neurologimentioning

confidence: 99%

Mitochondrial transport serves as a mitochondrial quality control strategy in axons: Implications for central nervous system disorders

2019

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Summary Axonal mitochondrial quality is essential for neuronal health and functions. Compromised mitochondrial quality, reflected by loss of membrane potential, collapse of ATP production, abnormal morphology, burst of reactive oxygen species generation, and impaired Ca 2+ buffering capacity, can alter mitochondrial transport. Mitochondrial transport in turn maintains axonal mitochondrial homeostasis in several ways. Newly generated mitochondria are anterogradely transported along with axon from soma to replenish axonal mitochondrial pool, while damaged mitochondria undergo retrograde transport for repair or degradation. Besides, mitochondria are also arrested in axon to quarantine damages locally. Accumulating evidence suggests abnormal mitochondrial transport leads to mitochondrial dysfunction and axon degeneration in a variety of neurological and psychiatric disorders. Further investigations into the details of this process would help to extend our understanding of various neurological diseases and shed light on the corresponding therapies.

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Phosphoregulation of Tau modulates inhibition of kinesin-1 motility

Cited by 59 publications

References 38 publications

Tau directs intracellular trafficking by regulating the forces exerted by kinesin and dynein teams

Tau directs intracellular trafficking by regulating the forces exerted by kinesin and dynein teams

ReMAPping the microtubule landscape: How phosphorylation dictates the activities of microtubule‐associated proteins

Mitochondrial transport serves as a mitochondrial quality control strategy in axons: Implications for central nervous system disorders

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