Composition of Rosenthal Fibers, the Protein Aggregate Hallmark of Alexander Disease

Heaven, Michael R.; Flint, Daniel; Randall, Shan M.; Sosunov, Alexander A.; Wilson, Landon; Barnes, Stephen; Goldman, James E.; Muddiman, David C.; Brenner, Michael

doi:10.1021/acs.jproteome.6b00316

Cited by 37 publications

(43 citation statements)

References 66 publications

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“…To probe the direct connection between GFAP and the actin cytoskeleton in Alexander disease, we focused on the spectraplakin proteins, a family of giant cytoskeletal linker proteins, which interact with F-actin and intermediate filaments 34 . Levels of the spectraplakin protein plectin are increased in Alexander disease patients and plectin co-localizes to the characteristic inclusion body of Alexander disease, the Rosenthal fiber 16 . To determine whether GFAP promotes F-actin stabilization through spectraplakin, we took advantage of the Drosophila model of Alexander disease.…”

Section: Resultsmentioning

confidence: 99%

“…The mouse and Drosophila models we use recapitulate Rosenthal fiber formation in affected glia. Although, Rosenthal fibers are typically associated with intermediate filaments, not thin actin filaments, when assessed by electron microscopy, proteomic and immunolocalization experiments demonstrate that the spectraplakin linker protein plectin and actin 16 are closely associated with inclusions and thus may mediate an interaction between Rosenthal fibers and the actin cytoskeleton (Fig. 6d ).…”

Section: Discussionmentioning

confidence: 99%

“…Rosenthal fibers are also commonly seen in the context of longstanding, dense reactive gliosis in human brains. Similarly, significant overexpression of human wild-type GFAP in mice causes Rosenthal fiber formation, and models other aspects of Alexander disease as well 11 – 16 , raising the possibility that persistently elevated levels of wild-type human GFAP may cause cellular toxicity in some human brain disorders. However, increased levels of GFAP can also be observed in astrocytes that subserve protective functions, indicating a complex cellular interplay of neuroprotective and neurotoxic roles of astrocytes in normal and disease states 17 – 20 .…”

Section: Introductionmentioning

confidence: 99%

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Tissue and cellular rigidity and mechanosensitive signaling activation in Alexander disease

Wang

Xia

et al. 2018

Nat Commun

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Glial cells have increasingly been implicated as active participants in the pathogenesis of neurological diseases, but critical pathways and mechanisms controlling glial function and secondary non-cell autonomous neuronal injury remain incompletely defined. Here we use models of Alexander disease, a severe brain disorder caused by gain-of-function mutations in GFAP, to demonstrate that misregulation of GFAP leads to activation of a mechanosensitive signaling cascade characterized by activation of the Hippo pathway and consequent increased expression of A-type lamin. Importantly, we use genetics to verify a functional role for dysregulated mechanotransduction signaling in promoting behavioral abnormalities and non-cell autonomous neurodegeneration. Further, we take cell biological and biophysical approaches to suggest that brain tissue stiffness is increased in Alexander disease. Our findings implicate altered mechanotransduction signaling as a key pathological cascade driving neuronal dysfunction and neurodegeneration in Alexander disease, and possibly also in other brain disorders characterized by gliosis.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tissue and cellular rigidity and mechanosensitive signaling activation in Alexander disease

Wang

Xia

et al. 2018

Nat Commun

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“…The brain pathology of the boy showed “progressive fibrinoid degeneration of fibrillary astrocytes,” [ 6 ] which was later identified as Rosenthal fibers that were initially described by Werner Rosenthal in ependymoma in 1898 [ 7 ]. Rosenthal fibers are homogeneous eosinophilic inclusions stained by hematoxylin and eosin, and consist mainly of glial fibrillary acidic protein (GFAP), αB-crystallin, heat shock protein (HSP) 27 and cyclin D2 [ 2 , 3 , 5 ]. Messing and colleagues reported that AxD was elicited by mutations in the gene encoding GFAP, a type III intermediate filament predominantly found in astrocytes.…”

Section: Introductionmentioning

confidence: 99%

Aggregation-prone GFAP mutation in Alexander disease validated using a zebrafish model

et al. 2017

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BackgroundAlexander disease (AxD) is an astrogliopathy that predominantly affects the white matter of the central nervous system (CNS), and is caused by a mutation in the gene encoding the glial fibrillary acidic protein (GFAP), an intermediate filament primarily expressed in astrocytes and ependymal cells. The main pathologic feature of AxD is the presence of Rosenthal fibers (RFs), homogeneous eosinophilic inclusions found in astrocytes. Because of difficulties in procuring patient’ CNS tissues and the presence of RFs in other pathologic conditions, there is a need to develop an in vivo assay that can determine whether a mutation in the GFAP results in aggregation and is thus disease-causing.MethodsWe found a GFAP mutation (c.382G > A, p.Asp128Asn) in a 68-year-old man with slowly progressive gait disturbance with tendency to fall. The patient was tentatively diagnosed with AxD based on clinical and radiological findings. To develop a vertebrate model to assess the aggregation tendency of GFAP, we expressed several previously reported mutant GFAPs and p.Asp128Asn GFAP in zebrafish embryos.ResultsThe most common GFAP mutations in AxD, p.Arg79Cys, p.Arg79His, p.Arg239Cys and p.Arg239His, and p.Asp128Asn induced a significantly higher number of GFAP aggregates in zebrafish embryos than wild-type GFAP.ConclusionsThe p.Asp128Asn GFAP mutation is likely to be a disease-causing mutation. Although it needs to be tested more extensively in larger case series, the zebrafish assay system presented here would help clinicians determine whether GFAP mutations identified in putative AxD patients are disease-causing.

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“…We also do not distinguish between the GFAP-␣ and GFAP-␦ isoforms, although ␣ likely represents more than ϳ90% of the total in the CNS (42,43). Differences in solubility exist between the GFAP isoforms and between mutant and wild-type protein (39,41,44,45), although not under the conditions used for extraction in the experiments reported here.…”

Section: Discussionmentioning

confidence: 77%

Glial fibrillary acidic protein exhibits altered turnover kinetics in a mouse model of Alexander disease

Moody

Barrett-Wilt

Sussman

et al. 2017

Journal of Biological Chemistry

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Edited by George N. DeMartinoMutations in the astrocyte-specific intermediate filament glial fibrillary acidic protein (GFAP) lead to the rare and fatal disorder, Alexander disease (AxD). A prominent feature of the disease is aberrant accumulation of GFAP. It has been proposed that this accumulation occurs because of an increase in gene transcription coupled with impaired proteasomal degradation, yet this hypothesis remains untested. We therefore sought to directly investigate GFAP turnover in a mouse model of AxD that is heterozygous for a disease-causing point mutation (Gfap R236H/؉ ) (and thus expresses both wild-type and mutant protein). Stable isotope labeling by amino acids in cell culture, using primary cortical astrocytes, indicated that the in vitro halflives of total GFAP in astrocytes from wild-type and mutant mice were similar at ϳ3-4 days. Surprisingly, results obtained with stable isotope labeling of mammals revealed that, in vivo, the half-life of GFAP in mutant mice (15.4 ؎ 0.5 days) was much shorter than that in wild-type mice (27.5 ؎ 1.6 days). These unexpected in vivo data are most consistent with a model in which synthesis and degradation are both increased. Our work reveals that an AxD-causing mutation alters GFAP turnover kinetics in vivo and provides an essential foundation for future studies aimed at preventing or reducing the accumulation of GFAP. In particular, these data suggest that elimination of GFAP might be possible and occurs more quickly than previously surmised.Alexander disease (AxD) 2 is a rare and often fatal human disease of the central nervous system caused by dominant mutations in the astrocyte intermediate filament glial fibrillary acidic protein (GFAP) (1). Most AxD patients have de novo mutations in GFAP (2), encoding for various missense mutations as well as small in-frame insertions and deletions. The hallmark feature of the pathology is the formation of aggregates, known as Rosenthal fibers (RFs), within the cell bodies and processes of astrocytes, along with variable degrees of white matter deficits. Although the genetic basis for AxD is clear, the mechanisms by which GFAP mutations lead to astrocyte dysfunction and the cascade of secondary effects on other cells in the central nervous system remain unresolved. Previous studies demonstrated that simple overexpression of wild-type GFAP to high levels induces the formation of RFs (3), and indeed increased levels of GFAP are consistently present in autopsy samples from patients with AxD (4 -8). Mouse models engineered to express mutations equivalent to common human mutations (9) illustrate a connection between GFAP levels and severity of disease, which has led to the concept of "GFAP toxicity."The excessive accumulation of GFAP and the formation of RFs in AxD presumably reflect a fundamental alteration in proteostasis. Proteostasis, or protein homeostasis, involves a vast network of pathways that control protein synthesis, folding, trafficking, aggregation, and degradation. Protein aggregation disorders such as Alzhei...

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Composition of Rosenthal Fibers, the Protein Aggregate Hallmark of Alexander Disease

Cited by 37 publications

References 66 publications

Tissue and cellular rigidity and mechanosensitive signaling activation in Alexander disease

Tissue and cellular rigidity and mechanosensitive signaling activation in Alexander disease

Aggregation-prone GFAP mutation in Alexander disease validated using a zebrafish model

Glial fibrillary acidic protein exhibits altered turnover kinetics in a mouse model of Alexander disease

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