Hook Proteins: Association with Alzheimer Pathology and Regulatory Role of Hook3 in Amyloid Beta Generation

Herrmann, Lydia; Wiegmann, Caspar; Arsalan-Werner, Annika; Hilbrich, Isabel; Jäger, Carsten; Flach, Katharina; Suttkus, Anne; Lachmann, Ingolf; Arendt, Thomas; Holzer, Max

doi:10.1371/journal.pone.0119423

Cited by 22 publications

(15 citation statements)

References 52 publications

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“…Hook1 and Hook3, the two isoforms pulled down by Rab5A, are expressed predominantly in neurons, whereas Hook2 is expressed mainly in astrocytes (71). Imaging of live neurons and kymograph analysis showed that mCherry-labeled forms of both Hook1 and Hook3, as well as FHIP-mCherry, colocalized with GFP-Rab5A on axonal retrograde carriers (Fig.…”

Section: Rab5 Is Required For Somatodendritic Sorting Of Glutamate Rementioning

confidence: 90%

Rab5 and its effector FHF contribute to neuronal polarity through dynein-dependent retrieval of somatodendritic proteins from the axon

Guo

Farı́as

Mattera

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

105

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An open question in cell biology is how the general intracellular transport machinery is adapted to perform specialized functions in polarized cells such as neurons. Here we illustrate this adaptation by elucidating a role for the ubiquitous small GTPase Ras-related protein in brain 5 (Rab5) in neuronal polarity. We show that inactivation or depletion of Rab5 in rat hippocampal neurons abrogates the somatodendritic polarity of the transferrin receptor and several glutamate receptor types, resulting in their appearance in the axon. This loss of polarity is not caused primarily by increased transport from the soma to the axon but rather by decreased retrieval from the axon to the soma. Retrieval is also dependent on the Rab5 effector Fused Toes (FTS)-Hook-FTS and Hook-interacting protein (FHIP) (FHF) complex, which interacts with the minus-enddirected microtubule motor dynein and its activator dynactin to drive a population of axonal retrograde carriers containing somatodendritic proteins toward the soma. These findings emphasize the importance of both biosynthetic sorting and axonal retrieval for the polarized distribution of somatodendritic receptors at steady state.Rab5 | FHF complex | dynein | neuronal polarity | retrograde transport N eurons are highly polarized cells with distinct somatodendritic and axonal domains. Synaptic inputs are received through the somatodendritic domain, integrated at the axon initial segment (AIS), and propagated along the axon for transmission to downstream cells. To accomplish these specialized functions, each neuronal domain is endowed with a distinct set of proteins. A fundamental but still largely unanswered question is how neurons establish and maintain this polarized distribution of proteins throughout their lifetimes. The available evidence indicates that the mechanisms of polarized sorting in neurons are quite complex (1-3). Newly synthesized transmembrane proteins travel together from their site of synthesis in the rough endoplasmic reticulum (ER) to the Golgi complex. Once they reach the trans-Golgi network (TGN), the proteins are sorted into different membraneenclosed transport carriers destined for the somatodendritic or axonal domains (4-8). However, the efficiency of this biosynthetic sorting varies for different proteins and is often incomplete. Other processes, such as compartment-specific retention, retrieval, or transcytosis, additionally contribute to establishing the overall distribution of proteins between the somatodendritic and axonal domains and to their localization to specialized subdomains (5, 9-17).The selective incorporation of transmembrane proteins into specialized transport carriers is a key event in the mechanisms of polarized sorting. In some cases this process is mediated by recognition of sorting signals in the cytosolic tails of the proteins by components of protein coats associated with the cytosolic face of the donor compartment. One of the best-documented examples is the sorting of various transmembrane proteins to the somatodendritic domain...

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Section: Rab5 Is Required For Somatodendritic Sorting Of Glutamate Rementioning

confidence: 90%

Rab5 and its effector FHF contribute to neuronal polarity through dynein-dependent retrieval of somatodendritic proteins from the axon

Guo

Farı́as

Mattera

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

105

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“…It remains to be determined how Hook proteins play a role in intracellular trafficking in more specialized cells like neurons. A recent study linked Hook proteins to Alzheimer disease, showing decreased levels of Hook proteins in diseased brains, and localized these proteins to the pathological hallmarks of Alzheimer disease, tau aggregates and amyloid plaques (45). Future work is needed to better understand the role of these adaptors in intracellular trafficking under both normal conditions and in disease states like Alzheimer disease.…”

Section: Discussionmentioning

confidence: 99%

Hook Adaptors Induce Unidirectional Processive Motility by Enhancing the Dynein-Dynactin Interaction

Olenick

Tokito²,

Boczkowska³

et al. 2016

Journal of Biological Chemistry

106

146

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Cytoplasmic dynein drives the majority of minus end-directed vesicular and organelle motility in the cell. However, it remains unclear how dynein is spatially and temporally regulated given the variety of cargo that must be properly localized to maintain cellular function. Recent work has suggested that adaptor proteins provide a mechanism for cargo-specific regulation of motors. Of particular interest, studies in fungal systems have implicated Hook proteins in the regulation of microtubule motors. Here we investigate the role of mammalian Hook proteins, Hook1 and Hook3, as potential motor adaptors. We used optogenetic approaches to specifically recruit Hook proteins to organelles and observed rapid transport of peroxisomes to the perinuclear region of the cell. This rapid and efficient translocation of peroxisomes to microtubule minus ends indicates that mammalian Hook proteins activate dynein rather than kinesin motors. Biochemical studies indicate that Hook proteins interact with both dynein and dynactin, stabilizing the formation of a supramolecular complex. Complex formation requires the N-terminal domain of Hook proteins, which resembles the calponin-homology domain of end-binding (EB) proteins but cannot bind directly to microtubules. Single-molecule motility assays using total internal reflection fluorescence microscopy indicate that both Hook1 and Hook3 effectively activate cytoplasmic dynein, inducing longer run lengths and higher velocities than the previously characterized dynein activator bicaudal D2 (BICD2). Together, these results suggest that dynein adaptors can differentially regulate dynein to allow for organellespecific tuning of the motor for precise intracellular trafficking.Microtubules provide a polarized highway to facilitate the transport of organelles and vesicles throughout the cell. The minus ends of microtubules are usually nucleated near the cell center, with the plus ends oriented outward, toward the cell periphery. This polarity ensures that microtubule motors drive motility in a specific direction; kinesin motors generally drive plus end motility, whereas minus end traffic is primarily driven by cytoplasmic dynein. Regulation of these opposing motors is vital for cell survival, particularly in specialized cells like neurons that require efficient transport over long distances (1). However, it remains unclear how microtubule motors are spatially and temporally regulated to control the intracellular trafficking of specific cargo. As a single major form of cytoplasmic dynein drives the transport of a wide array of cargos, including endosomes, RNA granules, and mitochondria (2-4), it is likely that the transport properties of dynein are modulated by the binding of cargo-specific adaptor molecules.

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“…In the AD brain, reduction in Hook 3 expression and increase in Hook 2 mRNA levels have been observed. Interestingly, when Hook 3 is knocked down, there is an increase in Aβ production ( 38 ). While there are three forms of Hook in humans, only one form of Hook has been reported in Drosophila.…”

Section: Resultsmentioning

confidence: 99%

“…There is strong evidence to confirm the association of autophagy dysregulation with AD ( 54 ). Herrmann and colleagues showed that Hook3 was co-localized with tau aggregate and retained in those aggregates ( 38 ). Surprisingly, in our current research, there was a remarkable increase in the levels of dHook expression in 25-day-old flies expressing Tau R406W.…”

Section: Discussionmentioning

confidence: 99%

Distinctive alteration in the expression of autophagy genes in Drosophila models of amyloidopathy and tauopathy

Haghi

Masoudi

Najibi

2020

Upsala Journal of Medical Sciences

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Background: Alzheimer's disease (AD) is one the most common types of dementia. Plaques of amyloid beta and neurofibrillary tangles of tau are two major hallmarks of AD. Metabolism of these two proteins, in part, depends on autophagy pathways. Autophagy dysfunction and protein aggregation in AD may be involved in a vicious circle. The aim of this study was to investigate whether tau or amyloid beta 42 (Ab42) could affect expression of autophagy genes, and whether they exert their effects in the same way or not. Methods: Expression levels of some autophagy genes, Hook, Atg6, Atg8, and Cathepsin D, were measured using quantitative PCR in transgenic Drosophila melanogaster expressing either Ab42 or Tau R406W. Results: We found that Hook mRNA levels were downregulated in Ab42-expressing flies both 5 and 25 days old, while they were increased in 25-day-old flies expressing Tau R406W. Both Atg6 and Atg8 were upregulated at day 5 and then downregulated in 25-day-old flies expressing either Ab42 or Tau R406W. Cathepsin D expression levels were significantly increased in 5-day-old flies expressing Tau R406W, while there was no significant change in the expression levels of this gene in 5-day-old flies expressing Ab42. Expression levels of Cathepsin D were significantly decreased in 25-day-old transgenic flies expressing Tau R406W or Ab42. Conclusion: We conclude that both Ab42 and Tau R406W may affect autophagy through dysregulation of autophagy genes. Interestingly, it seems that these pathological proteins exert their toxic effects on autophagy through different pathways and independently.

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Hook Proteins: Association with Alzheimer Pathology and Regulatory Role of Hook3 in Amyloid Beta Generation

Cited by 22 publications

References 52 publications

Rab5 and its effector FHF contribute to neuronal polarity through dynein-dependent retrieval of somatodendritic proteins from the axon

Rab5 and its effector FHF contribute to neuronal polarity through dynein-dependent retrieval of somatodendritic proteins from the axon

Hook Adaptors Induce Unidirectional Processive Motility by Enhancing the Dynein-Dynactin Interaction

Distinctive alteration in the expression of autophagy genes in Drosophila models of amyloidopathy and tauopathy

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