Requirements for Hirano Body Formation

Griffin, Paul; Furukawa, Ruth; Piggott, Cleveland; Maselli, Andrew; Fechheimer, Marcus

doi:10.1128/ec.00044-14

Cited by 11 publications

(14 citation statements)

References 60 publications

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“…F-actin in model Hirano bodies formed in Dictyostelium with the gain-of-function 34 kDa mutant E60K are very stable in the presence of latrunculin A. The F-actin content of the model Hirano body measured by the fluorescence of rhodamine-labeled phalloidin decreased 31% after 2 hours [50]. This increased F-actin stability could cause spines to form and refashion more slowly, thus impacting memory functions.…”

Section: Effect Of Hirano Bodies In the Dorsal Versus Ventral Hippocamentioning

confidence: 96%

“…These smaller structures have also been noted in the brains of humans [48] and in the brains of R26CT-CRE mice (Additional file 2: Figure S2 C). In Dictyostelium, small nascent model Hirano body structures observed by TEM fuse together by an unknown process involving microtubules and myosin II to form larger Hirano bodies [21,49,50]. It is likely that a similar formation process of Hirano bodies is occurring in R26CT-CRE mouse brains since several small aggregates can be seen in close proximity in TEM samples (Additional file 2: Figure S2 C).…”

Section: Incidence and Ultrastructure Of Hirano Bodies In Transgenic mentioning

confidence: 99%

“…Mutant forms of the Dictyostelium 34 kDa actin bundling protein are gain-of-function actin bundling proteins that induce the formation of model Hirano bodies [21,73,50]. Expression of these proteins causes a shift in the ratio of F:G-actin in the cell [21], and slower turnover of actin filaments in the model Hirano body [50]. Thus, the presence of model Hirano bodies cause a large perturbation to the actin cytoskeleton and potentially to synaptic functions and memory.…”

Section: The Effect Of Model Hirano Bodies On Synaptic Plasticitymentioning

confidence: 99%

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Hirano body expression impairs spatial working memory in a novel mouse model

Furgerson

Clark

Crystal

et al. 2014

Acta Neuropathologica Communications

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Introduction: Hirano bodies are actin-rich intracellular inclusions found in the brains of patients with neurodegenerative conditions such as Alzheimer's disease or frontotemporal lobar degeneration-tau. While Hirano body ultrastructure and protein composition have been well studied, little is known about the physiological function of Hirano bodies in an animal model system. Results: Utilizing a Cre/Lox system, we have generated a new mouse model which develops an age-dependent increase in the number of model Hirano bodies present in both the CA1 region of the hippocampus and frontal cortex. These mice develop normally and experience no overt neuron loss. Mice presenting model Hirano bodies have no abnormal anxiety or locomotor activity as measured by the open field test. However, mice with model Hirano bodies develop age-dependent impairments in spatial working memory performance assessed using a delayed win-shift task in an 8-arm radial maze. Synaptic transmission, short-term plasticity, and long-term plasticity was measured in the CA1 region from slices obtained from both the ventral and dorsal hippocampus in the same mice whose spatial working memory was assessed. Baseline synaptic responses, paired pulse stimulation and long-term potentiation measurements in the ventral hippocampus were indistinguishable from control mice. In contrast, in the dorsal hippocampus, synaptic transmission at higher stimulus intensities were suppressed in 3 month old mice with Hirano bodies as compared with control mice. In addition, long-term potentiation was enhanced in the dorsal hippocampus of 8 month old mice with Hirano bodies, concurrent with observed impairment of spatial working memory. Finally, an inflammatory response was observed at 8 months of age in mice with Hirano bodies as assessed by the presence of reactive astrocytes. Conclusion: This study shows that the presence of model Hirano bodies initiates an inflammatory response, alters hippocampal synaptic responses, and impairs spatial working memory in an age-dependent manner. This suggests that Hirano bodies may promote disease progression. This new model mouse provides a tool to investigate how Hirano bodies interact with other pathologies associated with Alzheimer's disease. Hirano bodies likely play a complex and region specific role in the brain during neurodegenerative disease progression.

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Section: Effect Of Hirano Bodies In the Dorsal Versus Ventral Hippocamentioning

confidence: 96%

Section: Incidence and Ultrastructure Of Hirano Bodies In Transgenic mentioning

confidence: 99%

Section: The Effect Of Model Hirano Bodies On Synaptic Plasticitymentioning

confidence: 99%

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Hirano body expression impairs spatial working memory in a novel mouse model

Furgerson

Clark

Crystal

et al. 2014

Acta Neuropathologica Communications

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“…Hyperphosphorylated tau protein is deposited in a form referred to as neurofibrillary tangles (NFTs), leading to neuronal death (2). Other neuropathological changes found in AD include Hirano acid-absorbing bodies, which contain actin (16). Much of the recent research on AD has been focused on neurons, but recent studies suggest that glial cells, i.e.…”

Section: Formation Of the Myelin Sheathmentioning

confidence: 99%

Oligodendrocytes: Morphology, functions and involvement in neurodegenerative diseases

Krawczyk-Marć¹,

Wawrzyniak²,

Łuszczewska-Sierakowska³

et al. 2019

Medycyna Weterynaryjna

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Oligodendrocytes (OLs) are myelinating cells of the central nervous system (CNS). They are a highly specialized type of glial cell in the CNS of vertebrates, which guarantee the transmission of action potentials over long distances by producing a myelin sheath that wraps adjacent axons. Although they are often credited merely with participation in myelination, recent research has led to a radical change in the understanding the role of these glial cells. OLs are currently understood to be plastic and adaptive cells, capable of responding quickly to changes taking place in the spatial neuronal network in the CNS. Due to their complex differentiation process and their physiology, OLs are among the most sensitive cells in the CNS. Finding answers about their interactions with other types of glial cells may result in benefits in the form of neuroprotection and axon plasticity. Damage to OLs and the myelin sheath is one of processes contributing to the development of crippling neurological diseases, although the role of these cells in neurodegeneration remains controversial. This article not only presents OLs as cells whose ultimate goal is to produce myelin sheaths, but also discusses their involvement in neurodegenerative diseases.

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“…Models to study Hirano bodies in living cells were developed by expressing altered forms of a 34 kDa Dictyostelium actin-binding protein in Dictyostelium and mammalian cell lines ( Davis et al, 2008 ; Maselli et al, 2002 , 2003 ) and mice ( Furgerson et al, 2014 ; Ha et al, 2011b ). These altered forms exhibit gain-of-function activated F-actin binding ( Griffin et al, 2014 ; Maselli et al, 2002 , 2003 ). Proteins present in Hirano bodies in postmortem tissues were also found in model Hirano bodies ( Davis et al, 2008 ; Furgerson et al, 2012 ; Ha et al, 2011a ; Maselli et al, 2002 , 2003 ; Spears et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

De novoactin polymerization is required for model Hirano body formation inDictyostelium

et al. 2016

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Hirano bodies are eosinophilic, actin-rich inclusions found in autopsied brains in numerous neurodegenerative diseases. The mechanism of Hirano body formation is unknown. Mass spectrometry analysis was performed to identify proteins from partially purified model Hirano bodies from Dictyostelium. This analysis identified proteins primarily belonging to ribosomes, proteasomes, mitochondria and cytoskeleton. Profilin, Arp/2/3 and WASH identified by mass spectrometry were found to colocalise with model Hirano bodies. Due to their roles in actin regulation, we selected these proteins for further investigation. Inhibition of the Arp2/3 complex by CK666 prevented formation of model Hirano bodies. Since Arp2/3 activation occurs via the WASH or WAVE complex, we next investigated how these proteins affect Hirano body formation. Whereas model Hirano bodies could form in WASH-deficient cells, they failed to form in cells lacking HSPC300, a member of the WAVE complex. We identified other proteins required for Hirano body formation that include profilin and VASP, an actin nucleation factor. In the case of VASP, both its G- and F-actin binding domains were required for model Hirano body formation. Collectively, our results indicate that de novo actin polymerization is required to form model Hirano bodies.

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Requirements for Hirano Body Formation

Cited by 11 publications

References 60 publications

Hirano body expression impairs spatial working memory in a novel mouse model

Hirano body expression impairs spatial working memory in a novel mouse model

Oligodendrocytes: Morphology, functions and involvement in neurodegenerative diseases

De novoactin polymerization is required for model Hirano body formation inDictyostelium

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