Introduction
Protein aggregation, inflammation, and oxidative stress are common hallmarks of neurodegenerative diseases of diverse etiology, both common and rare. Among the latter, Alexander disease (ALXDRD in OMIM, #203450, commonly abbreviated as AxD in the scientific literature) is a fatal neurodegenerative disorder that often disrupts the white matter of the brain and hence is classified as a leukodystrophy. Its clinical manifestations may include severe motor impairment and intellectual disability, epilepsy, megalencephaly, and seizures (Messing, 2018a; Figure 1). While seizures and macrocephaly seem more common in infantile than in adult onset of AxD, palatal myoclonus has been only described in the later form of the disease (Brenner et al., 2009; Balbi et al., 2010). The cause of AxD are mostly de novo mutations in glial fibrillary acidic protein (GFAP), a type III intermediate filament protein expressed mainly in astrocytes, which are key players in brain function and homeostasis (Pekny et al., 2016; Messing, 2018a). However, some cases of inherited pathogenic mutations have been also reported (Li et al., 2006; Zang et al., 2013). The continuously increasing number of reported GFAP mutations associated with AxD can be found in a dedicated database supported and updated by Messing’s group (https://alexander-disease.waisman.wisc.edu).
;)
Figure 1: Main events occurring in AxD at the brain, cellular and protein levels, with special consideration of various types of stress as factors potentially involved in the pathogenesis or progression of the disease.ATP: Adenosine triphosphate; GFAP: glial fibrillary acidic protein.
AxD mutations are mainly heterozygous single-point substitutions, which can occur at diverse locations in the GFAP sequence. Remarkably, the mutant proteins display a dominant behavior disrupting the assembly of the intermediate filament network and eliciting the formation of characteristic protein aggregates, known as Rosenthal fibers, in the cytoplasm of astrocytes. Rosenthal fibers may contain not only GFAP, but also a variety of other proteins involved among others in stress response (e.g., αB-crystallin and Hsp27) (Iwaki et al., 1989; Der Perng et al., 2006), transcription (e.g., cJun) (Tang et al., 2006), and protein degradation (e.g. ubiquitin, proteasome 20S) (Lowe et al., 1988; Tang et al., 2010), together with other intermediate filament proteins and factors regulating their assembly (e.g., plectin, synemin, vimentin) (Tian et al., 2006; Pekny et al., 2014; Heaven et al., 2016). Either due to the impairment of supporting functions or toxic effects of astrocytes carrying mutant GFAP, intercellular communication with neurons, and putatively with oligodendrocytes forming the myelin around axons, and brain homeostasis are compromised in AxD leading to neurodegeneration. In this line, nitric oxide release from astrocytes has been shown to trigger neurodegeneration in an experimental model of AxD (Wang et al., 2015). Nevertheless, the molecular pathogenesis of AxD remains largely unknown. Therefore, more detailed studies on specific GFAP mutants associated with different AxD types/onsets are needed. Here we will summarize the current knowledge on several aspects of AxD emphasizing those that, in our opinion, deserve a stronger research effort in the near future.
Glial Fibrillary Acidic Protein Protein Structure and Regulation
The GFAP gene encodes the canonical GFAPα form spanning 432 residues, as well as several alternative spliced isoforms (Hol and Pekny, 2015; van Asperen et al., 2022), which differ mainly in their C-terminal end. GFAP consists of structurally disordered head and tail domains and a central coiled-coil rod domain containing the single cysteine residue (C294) of the protein. Assembly of type III intermediate filaments, as delineated in vitro, is believed to progress through the parallel alignment of the rod domains of two monomers leading to dimers, which further associate in an antiparallel fashion to render tetramers, eight of which assemble into unit length filaments (Etienne-Manneville, 2018). Consecutive unit length filaments connect the head to tail and compact radially to form mature filaments (Etienne-Manneville, 2018).
In cells, GFAP hetero-oligomerizes with vimentin (Vim) to form the dynamic network that extends from the cell membrane to the nuclear periphery, while establishing multiple interactions with various cellular structures. Loss of function studies in mice showed that GFAP and vimentin in astrocytes partially compensate for each other (Eliasson et al., 1999; Pekny et al., 1999), and thus, many revealing phenotypes of GFAP deficiency are apparent only in Gfap–/– mice on a Vim–/– background, i.e., in mice with astrocytes lacking both cytoplasmic intermediate filament proteins (reviewed in Ridge et al., 2022).
Both GFAP and vimentin are targets of a large variety of enzymatic and non-enzymatic posttranslational modifications that regulate their assembly and function (Etienne-Manneville, 2018). The GFAP and vimentin network establishes interactions with a multitude of proteins in various cellular structures and thus plays important roles in astrocyte migration, proliferation and organelle positioning and homeostasis. Moreover, the GFAP-vimentin organization is key for the mechanical resistance of the central nervous system to severe trauma, hypertrophy of astrocyte processes in central nervous system diseases, proper wound healing after brain and spinal cord trauma, determines neuroprotective functions of astrocytes in acute ischemic stroke, and affects post-stroke neuronal connectivity and functional recovery (reviewed in Ridge et al., 2022).
Glial Fibrillary Acidic Protein Misfolding and Aggregation in Alexander Disease
In the intricate and vastly multifaceted context of the nervous system, the variety of GFAP isoforms, their homo- or hetero-oligomerization, and different isoform ratios add additional complexity levels. Most of the work to date has been focused on the GFAPα isoform and its regulation, e.g. by phosphorylation or oxidative modifications (Inagaki et al., 1994; Viedma-Poyatos et al., 2020), while the same aspects remain either poorly analyzed or unknown for other GFAP isoforms. In this setting, the expression of AxD mutant GFAPs further confounds the picture. Importantly, the dose of mutant protein needed to perturb the wild-type (wt) GFAP network poses a relevant issue, considering that even wt GFAP displays a propensity to misfold when expressed at high levels (Messing et al., 1998). The latest data suggest diverse expression ratios between wt and distinct mutant GFAPs to attain network disruption (Heaven et al., 2019; Kang et al., 2022; Yang et al., 2022), a subject that requires further investigation.
The appearance of cytoplasmic protein aggregates upon expression of AxD mutants and their accumulation as ubiquitinated forms, already suggests a proteostasis problem, likely involving misfolding, misassembly, and/or impaired degradation (Figure 2). While the similarity in sequence and secondary structure of vimentin and wt GFAP indicates an analogous assembly pathway from monomers into higher order oligomers and filaments, the monomer folding pathway has not been studied in detail for any GFAP isoform. Hence, a deeper knowledge of the GFAP folding pathway, its intermediates, and their dependence on context factors, such as the redox state, metals, pH, etc., is required to fully comprehend the impact of the mutations. The folding pathway may be altered differentially by each mutation and, if this is the case, the intermediates formed may or may not allow progression into the final “correct” monomer structure. Unproductive intermediates, those that do not reach the final “correct” monomer structure, could just accumulate and associate with a variety of proteins, giving rise to aggregates that may not be necessarily identical in composition and pathogenic significance. Another putative scenario may arise when the folding of mutant GFAPs progresses into the “correct” final monomer structure, but with local changes in charge, exposure, or orientation of side chains that may disturb the subsequent assembly process.
Figure 2: Comparison of the features of wild type and AxD mutant GFAP.Images at the top illustrate the morphological appearance of GFAP wild-type filaments (left) and of the assemblies formed by a R239C AxD mutant (right), upon expression in a cellular model of AxD. Note the uniform appearance of the intermediate filament network (left) and the alterations, including bundles and aggregates, characteristic of cells expressing AxD GFAP (right). The table at the bottom summarizes the main network and protein features under both conditions. For more details, please see (Viedma-Poyatos et al., 2022). AxD: Alexander disease; GFAP: glial fibrillary acidic protein. Unpublished data.
Posttranslational Modifications and Protein Interactions of Glial Fibrillary Acidic Protein and Their Alterations in Alexander Disease
Detection of high molecular weight forms of GFAP AxD mutants, resistant under various denaturing conditions, suggests the occurrence of various posttranslational modifications, potentially including crosslinks (Viedma-Poyatos et al., 2022; Yang et al., 2022), although their detailed characterization is still lacking. Phosphorylation of GFAP has been identified at several positions in the protein sequence and it should be considered that AxD mutations may alter the accessibility of kinases and/or phosphatases to specific sites, in turn, changing the level and/or pattern of GFAP modification in the mutant forms. These alterations may affect another aspect of intermediate filaments, which is their dynamic nature and their subunit exchange that is regulated by phosphorylation. Fluorescence after photobleaching data have been obtained only for GFAPα and GFAPδ isoforms, the results indicating slower incorporation and dissociation of GFAPδ into the filament network (Moeton et al., 2016). However, to which point these aspects are altered by the presence of other GFAP isoforms or AxD mutants remains largely unknown.
AxD mutations may either eliminate or add target residues susceptible to posttranslational modification into GFAP, thus changing the posttranslational modification landscape and giving rise to proteoforms of unpredictable behavior. Mutants to cysteine, including R79C or R239C, causing severe forms of AxD, imply a duplication of the cysteine content in GFAP, putatively conferring the network a higher susceptibility to disruption by oxidative posttranslational modifications (Viedma-Poyatos et al., 2022). In contrast, mutants to histidine may offer other possibilities as targets for new types of phosphorylation, lipoxidation, or protein carbonyl formation. Additionally, crosstalk between diverse posttranslational modifications may be favored or precluded by the substitution of certain residues. In this line, the field lacks detailed information on the interplay between well-established posttranslational modifications identified in wt GFAP, such as phosphorylation, and non-enzymatic modifications, such as oxidation. Therefore, we are in a need of further proteomic studies to progress in the understanding of the consequences derived from AxD mutations.
GFAP establishes a large variety of protein-protein interactions that are being collected in several databases (e.g., BioGRID, https://thebiogrid.org/search.php?search=gfap&organism=all). To date, the available information refers mainly to the GFAPα isoform, although some data concerning GFAPδ interactions are also available. Nevertheless, to the best of our knowledge, no interactions for other GFAP isoforms have been reported. Moreover, the consequences of these protein-protein interactions are generally poorly understood. In this line, AxD-associated mutants in any GFAP isoform may alter the wild-type interaction network in ways that remain unknown. Hence, the need for interactomic studies to decipher the protein-protein interaction network for all the GFAP isoforms and their corresponding AxD mutations, to achieve a real comprehension of the normal behavior and its alterations in the disease.
Impact of Glial Fibrillary Acidic Protein Mutations on Organelle Function
Expression of certain AxD mutants in cellular models also disrupts organelle homeostasis altering the positioning, morphology, and function of cellular organelles, as well as astrocytic secretion (Jones et al., 2018; Viedma-Poyatos et al., 2022). Effects of AxD mutants on organelles such as the mitochondria have been shown upon expression of some of these mutants in astrocytoma cells (Viedma-Poyatos et al., 2022). In this setting, oxidative stress was found, mainly due to the increased generation of mitochondrial ROS (Viedma-Poyatos et al., 2022). Since mitochondria are key for ATP production, the oxidative stress induced by expression of the AxD mutants may, in turn, affect the whole astrocyte metabolism (Figure 1). Thus, the imbalance between synthesis through the electron transport chain and glycolysis, whether total or partial, may not alter total ATP levels but lead to important consequences in other essential metabolic pathways, as well as in regulatory mechanisms. ATP is necessary for intermediate filament dynamics. Moreover, ATP is required to maintain the high glutathione levels found in astrocytes (8–10 mM). Glutathione is exported to the extracellular compartment where it has been proposed to serve as the source of precursors for neuronal glutathione synthesis (reviewed in McBean, 2017). Although the precise mechanisms underlying this hypothetical glutathione “exchange” have not been elucidated, it can be envisioned that any alteration in astrocytic glutathione synthesis, would have consequences in the nearby neurons. Of note, expression of a GFAP R239C AxD mutant construct in astrocytoma cells already causes a decrease in intracellular free thiol content (Viedma-Poyatos et al., 2022), mainly representing reduced glutathione (Figure 1). Whether this occurs in cells expressing other AxD mutants, as well as in vivo, potentially affecting (nearby) neurons, deserves further research.
Changes in the redox potential due to oxidative stress can alter many aspects of cell function that rely on the introduction of posttranslational modifications in key proteins of signaling cascades (Corcoran and Cotter, 2013; Truong and Carroll, 2013), which subsequently may modify the final effector molecules (e.g. proteins, DNA) in diverse subcellular locations. In fact, these changes can alter both the levels and targets of posttranslational modifications in different organelles, leading to their anomalous function, location, and/or morphology. This is achieved through the increased production of the modifying compounds (e.g., electrophiles such as 4-HNE) (Muntane et al., 2006; Martinez et al., 2008; Di Domenico et al., 2014) or by inducing the oxidation of the enzymes carrying out the modifications (e.g., kinases), in turn, leading to their inhibition or activation (Behring et al., 2020; Byrne et al., 2020; Lim et al., 2020; Shrestha et al., 2020). In this context, changes in the astrocyte redox potential induced by the expression of certain AxD mutants as described by Viedma-Poyatos et al. (2022) could impose a series of consequences derived from e.g. oxidative-regulated posttranslational modifications putatively including epigenetic changes that depend on intermediates of redox metabolism (Cyr and Domann, 2011), which need to be explored.
The protein misfolding and aggregation of AxD mutants may be related to endoplasmic reticulum stress, a condition found in most neurodegenerative diseases, and impaired unfolded protein response (Hoozemans et al., 2012; Alberdi et al., 2013; Clayton and Popko, 2016; Duran-Aniotz et al., 2017; Smith et al., 2020; Figure 1). Additionally, altered vesicle trafficking leading to deficient ATP release has been described in cells expressing some AxD GFAP mutants (Jones et al., 2018), in turn, affecting intercellular communications with neurons (by Ca2+ waves). Whether there is a direct relationship between the GFAP network and these mechanisms remains to be elucidated.
Factors Contributing to Adult Onset of Alexander Disease
Although mutant GFAP alone can promote a situation of increased stress, as deduced from the analysis of patient samples, cultured astrocytes, and several models of AxD (discussed in Viedma-Poyatos et al., 2022), additional sources of stress could contribute to the onset and/or progression of the disease. Several reports have related onset of adult AxD or exacerbation of symptoms with endogenous or exogenous insults such as infections, fever, head trauma, or excessive alcohol consumption (Messing, 2018b). These stressors have in common that they can result in oxidative damage to the affected tissue. In fact, oxidative effects of long-term alcohol consumption have been reported in the adult brain (Collins and Neafsey, 2012), whereas hyperthermia induces oxidative stress in the nervous system of animal models (Chauderlier et al., 2017). In addition, there is extensive literature about how oxidative stress-derived damage occurring after traumatic brain injury affects the nervous tissue and can even hinder recovery (Rodriguez-Rodriguez et al., 2014). Therefore, oxidative stress could act as a potential inducer of the AxD pathology in individuals carrying GFAP mutations that have been asymptomatic until adulthood. In this respect, it is noteworthy that astrocytes from Gfap–/–Vim–/– mice that lack cytoplasmic intermediate filaments, as well as astrocytoma cells expressing AxD GFAP mutants, exhibit increased susceptibility to oxidative stress (de Pablo et al., 2013; Viedma-Poyatos et al., 2022; Figure 1). Being a rare disease, establishing a causal link between these factors and AxD would be challenging, and hence the experimental approaches to confirm such an association would be highly useful.
Experimental Models of Alexander Disease
Studies on AxD have used astrocytoma cell lines and primary astrocytes available from different repositories to explore the impact of a variety of GFAP mutants in cell function (Yang et al., 2022), as well as their susceptibility to modification (Viedma-Poyatos et al., 2018; Viedma-Poyatos et al., 2022). In addition, knock-in mouse (Hagemann et al., 2006), fly (Wang et al., 2015), and zebrafish models (Candiani et al., 2020), as well as neurospheres (Gomez-Pinedo et al., 2017), induced pluripotent stem cells (iPSCs) and their isogenic controls (Jones et al., 2018; Li et al., 2018; Battaglia et al., 2019; Gao et al., 2019) started to become available for research in this field. In fact, these models allowed to establish the role of AxD GFAP mutations in aspects such as altered glutamate transport (Tian et al., 2010), perturbation of organelle distribution (Jones et al., 2018), induction of autophagy (Tang et al., 2008a, b) or intercellular communication with neurons (Wang et al., 2015). However, none of these models fully recapitulated all the aspects of the disease.
To tackle the aspects that remain obscure in the GFAP field and AxD, the collection of experimental models already available is being expanded by the isolation of fibroblasts and derived iPSCs from additional patients carrying new GFAP mutations for further differentiation or reprogramming, the production of brain organoids, and animal models of AxD. These models will likely contribute to a better understanding of the pathogenic mechanisms and to the design of protective or therapeutic strategies for this disease. For detailed information on the experimental models available for the study of AxD, see the recent review by Hagemann (2022).
Therapeutic Approaches
From the clinical perspective, in lack of treatment, the therapeutic approaches employed to date are symptomatic and include antiepileptic drugs, supportive strategies, and surgical procedures, such as shunt surgery in case treatment of a hydrocephalous is needed. Nevertheless, there is no standard treatment. As the aberrant assembly is a common hallmark of mutant and excessive wt GFAP, most protective strategies explored to date have attempted to lower GFAP levels by targeting its expression. Among the compounds tested, phenytoin, carbamazepine, and curcumin used in cellular models of AxD normalized GFAP expression levels and improve folding and filament organization (Bachetti et al., 2012, 2021), while ceftriaxone decreased expression and induced elimination of mutant GFAP (Bachetti et al., 2010). Pexidartinib increased GFAP levels and decreased macrophage numbers in a mouse model of AxD (Boyd et al., 2021). Other strategies for AxD treatment were already discussed in several reviews (Messing et al., 2010; Hagemann, 2022). Importantly, antisense oligonucleotides decreasing GFAP expression have shown beneficial effects in a recently developed rat model, which seems to be superior to mouse models (Hagemann et al., 2021), and has aided the design of the first clinical trial with AxD patients (https://clinicaltrials.gov/search/term=Alexander%20Disease).
Conclusions and Future Directions
In spite of the advances made to date and the availability of new experimental models for AxD study, many aspects of the disease remain obscure or unknown. The role of the different GFAP isoforms and their impact on intermediate filament structure, and function remain unknown. Furthermore, it is needed to decipher how AxD mutations impact the synthesis of the isoforms, their structure and their ability to incorporate into the network. The impact of oxidative posttranslational modifications on wt and the mutated GFAPs is only starting to be studied and, given the ever-increasing variety of cellular posttranslational modifications, elucidating their role in AxD will require considerable effort. Effects on organelle positioning and function are also being progressively uncovered, but the number of AxD mutations is large enough to require the contribution of several research groups to get a complete understanding of the subject. The development of an efficient therapy will benefit from the data that are being obtained in vitro and from novel animal models.
Author contributions:MAP, EHG, MP and DPS wrote the manuscript. MAP, EHG and DPS carried out data search and preparation of illustrations. All authors approved the final version of the manuscript.
Conflicts of interest:The authors declare no conflicts of interest.
Data availability statement:No additional data are available.
C-Editors: Zhao M, Liu WJ, Qiu Y; T-Editor: Jia Y
References
1. Alberdi E, Wyssenbach A, Alberdi M, Sanchez-Gomez MV, Cavaliere F, Rodriguez JJ, Verkhratsky A, Matute C 2013 Ca(2+) -dependent endoplasmic reticulum stress correlates with astrogliosis in oligomeric amyloid beta-treated astrocytes and in a model of Alzheimer's disease. Aging Cell 12:292–302.
2. Bachetti T, Di Zanni E, Balbi P, Bocca P, Prigion I, Deiana GA, Rezzani A, Ceccherini I, Sechi G 2010 In vitro treatments with ceftriaxone promote elimination of mutant glial fibrillary acidic protein and transcription down-regulation. Exp Cell Res 316:2152–2165.
3. Bachetti T, Di Zanni E, Balbi P, Ravazzolo R, Sechi G, Ceccherini I 2012 Beneficial effects of curcumin on GFAP filament organization and down-regulation of GFAP expression in an in vitro model of Alexander disease. Exp Cell Res 318:1844–1854.
4. Bachetti T, Zanni ED, Adamo A, Rosamilia F, Sechi MM, Solla P, Bozzo M, Ceccherini I, Sechi G 2021 Beneficial effect of phenytoin and carbamazepine on GFAP gene expression and mutant GFAP folding in a cellular model of Alexander's disease. Front Pharmacol 12:723218.
5. Balbi P, Salvini S, Fundaro C, Frazzitta G, Maestri R, Mosah D, Uggetti C, Sechi G 2010 The clinical spectrum of late-onset Alexander disease:a systematic literature review. J Neurol 257:1955–1962.
6. Battaglia RA, Beltran AS, Delic S, Dumitru R, Robinson JA, Kabiraj P, Herring LE, Madden VJ, Ravinder N, Willems E, Newman RA, Quinlan RA, Goldman JE, Perng MD, Inagaki M, Snider NT 2019 Site-specific phosphorylation and caspase cleavage of GFAP are new markers of Alexander disease severity. Elife 8:e47789.
7. Behring JB, van der Post S, Mooradian AD, Egan MJ, Zimmerman MI, Clements JL, Bowman GR, Held JM 2020 Spatial and temporal alterations in protein structure by EGF regulate cryptic cysteine oxidation. Sci Signal 13:eaay7315.
8. Boyd MM, Litscher SJ, Seitz LL, Messing A, Hagemann TL, Collier LS 2021 Pexidartinib treatment in Alexander disease model mice reduces macrophage numbers and increases glial fibrillary acidic protein levels, yet has minimal impact on other disease phenotypes. J Neuroinflammation 18:67.
9. Brenner M, Goldman JE, Quinlan RA, Messing A 2009 Alexander disease:a genetic disorder of astrocytes. Astrocytes in (Patho)Physiology of the nervous system Parpura V, Haydon PG 591–648 New York Springer.
10. Byrne DP, Shrestha S, Galler M, Cao M, Daly LA, Campbell AE, Eyers CE, Veal EA, Kannan N, Eyers PA 2020 Aurora A regulation by reversible cysteine oxidation reveals evolutionarily conserved redox control of Ser/Thr protein kinase activity. Sci Signal 13:eaax2713.
11. Candiani S, Carestiato S, Mack AF, Bani D, Bozzo M, Obino V, Ori M, Rosamilia F, De Sarlo M, Pestarino M, Ceccherini I, Bachetti T 2020 Alexander disease modeling in zebrafish:an in vivo system suitable to perform drug screening. Genes (Basel) 11:1490.
12. Chauderlier A, Delattre L, Buee L, Galas MC 2017 In vivo hyperthermic stress model:an easy tool to study the effects of oxidative stress on neuronal tau functionality in mouse brain. Methods Mol Biol 1523:369–373.
13. Clayton BLL, Popko B 2016 Endoplasmic reticulum stress and the
unfolded protein response in disorders of myelinating glia. Brain Res 1648:594–602.
14. Collins MA, Neafsey EJ 2012 Ethanol and adult CNS neurodamage:oxidative stress, but possibly not excitotoxicity. Front Biosci (Elite Ed) 4:1358–1367.
15. Corcoran A, Cotter TG 2013 Redox regulation of protein kinases. FEBS J 280:1944–1965.
16. Cyr AR, Domann FE 2011 The redox basis of epigenetic modifications:from mechanisms to functional consequences. Antioxid Redox Signal 15:551–589.
17. de Pablo Y, Nilsson M, Pekna M, Pekny M 2013 Intermediate filaments are important for astrocyte response to oxidative stress induced by oxygen-glucose deprivation and reperfusion. Histochem Cell Biol 140:81–91.
18. Der Perng M, Su M, Wen SF, Li R, Gibbon T, Prescott AR, Brenner M, Quinlan RA 2006 The Alexander disease-causing glial fibrillary acidic protein mutant, R416W, accumulates into Rosenthal fibers by a pathway that involves filament aggregation and the association of alpha B-crystallin and HSP27. Am J Hum Genet 79:197–213.
19. Di Domenico F, Pupo G, Tramutola A, Giorgi A, Schinina ME, Coccia R, Head E, Butterfield DA, Perluigi M 2014 Redox proteomics analysis of HNE-modified proteins in Down syndrome brain:clues for understanding the development of Alzheimer disease. Free Radic Biol Med 71:270–280.
20. Duran-Aniotz C, Cornejo VH, Espinoza S, Ardiles AO, Medinas DB, Salazar C, Foley A, Gajardo I, Thielen P, Iwawaki T, Scheper W, Soto C, Palacios AG, Hoozemans JJM, Hetz C 2017 IRE1 signaling exacerbates Alzheimer's disease pathogenesis. Acta Neuropathol 134:489–506.
21. Eliasson C, Sahlgren C, Berthold CH, Stakeberg J, Celis JE, Betsholtz C, Eriksson JE, Pekny M 1999 Intermediate filament protein partnership in astrocytes. J Biol Chem 274:23996–24006.
22. Etienne-Manneville S 2018 Cytoplasmic intermediate filaments in cell biology. Annu Rev Cell Dev Biol 34:1–28.
23. Gao L, Zhang Z, Lu J, Pei G 2019 Mitochondria are dynamically transferring between human neural cells and alexander disease-associated GFAP mutations impair the astrocytic transfer. Front Cell Neurosci 13:316.
24. Gomez-Pinedo U, Sirerol-Piquer MS, Duran-Moreno M, Garcia-Verdugo JM, Matias-Guiu J 2017 Alexander disease mutations produce cells with coexpression of glial fibrillary acidic protein and NG2 in neurosphere cultures and inhibit differentiation into mature oligodendrocytes. Front Neurol 8:255.
25. Hagemann TL, Connor JX, Messing A 2006 Alexander disease-associated glial fibrillary acidic protein mutations in mice induce Rosenthal fiber formation and a white matter stress response. J Neurosci 26:11162–11173.
26. Hagemann TL, Powers B, Lin NH, Mohamed AF, Dague KL, Hannah SC, Bachmann G, Mazur C, Rigo F, Olsen AL, Feany MB, Perng MD, Berman RF, Messing A 2021 Antisense therapy in a rat model of Alexander disease reverses GFAP pathology, white matter deficits, and motor impairment. Sci Transl Med 13:eabg4711.
27. Hagemann TL 2022 Alexander disease:models, mechanisms, and medicine. Curr Opin Neurobiol 72:140–147.
28. Heaven MR, Flint D, Randall SM, Sosunov AA, Wilson L, Barnes S, Goldman JE, Muddiman DC, Brenner M 2016 Composition of rosenthal fibers, the protein aggregate hallmark of Alexander disease. J Proteome Res 15:2265–2282.
29. Heaven MR, Wilson L, Barne S, Brenner M 2019 Relative stabilities of wild-type and mutant glial fibrillary acidic protein in patients with Alexander disease. J Biol Chem 294:15604–15612.
30. Hol EM, Pekny M 2015 Glial fibrillary acidic protein (GFAP) and the astrocyte intermediate filament system in diseases of the central nervous system. Curr Opin Cell Biol 32:121–130.
31. Hoozemans JJ, van Haastert ES, Nijholt DA, Rozemuller AJ, Scheper W 2012 Activation of the
unfolded protein response is an early event in Alzheimer's and Parkinson's disease. Neurodegener Dis 10:212–215.
32. Inagaki M, Nakamura Y, Takeda M, Nishimura T, Inagaki N 1994 Glial fibrillary acidic protein:dynamic property and regulation by phosphorylation. Brain Pathol 4:239–243.
33. Iwaki T, Kume-Iwaki A, Liem RK, Goldman JE 1989 Alpha B-crystallin is expressed in non-lenticular tissues and accumulates in Alexander's disease brain. Cell 57:71–78.
34. Jones JR, Kong L, Hanna MGT, Hoffman B, Krencik R, Bradley R, Hagemann T, Choi J, Doers M, Dubovis M, Sherafat MA, Bhattacharyya A, Kendziorski C, Audhya A, Messing A, Zhang SC 2018 Mutations in GFAP disrupt the distribution and function of organelles in human astrocytes. Cell Rep 25:947–958.
35. Kang YR, Lee SH, Lin NH, Lee SJ, Yang AW, Chandrasekaran G, Kang KW, Jin MS, Kim MK, Perng MD, Choi SY, Nam TS 2022 A novel in-frame GFAP p.E138_L148del mutation in type II Alexander disease with atypical phenotypes. Eur J Hum Genet 30:687–694.
36. Li L, Tian E, Chen X, Chao J, Klein J, Qu Q, Sun G, Sun G, Huang Y, Warden CD, Ye P, Feng L, Li X, Cui Q, Sultan A, Douvaras P, Fossati V, Sanjana NE, Riggs AD, Shi Y 2018 GFAP mutations in astrocytes impair oligodendrocyte progenitor proliferation and myelination in an hiPSC model of Alexander disease. Cell Stem Cell 23:239–251.
37. Li R, Johnson AB, Salomons GS, van der Knaap MS, Rodriguez D, Boespflug-Tanguy O, Gorospe JR, Goldman JE, Messing A, Brenner M 2006 Propensity for paternal inheritance of de novo mutations in Alexander disease. Hum Genet 119:137–144.
38. Lim DC, Joukov V, Rettenmaier TJ, Kumagai A, Dunphy WG, Wells JA, Yaffe MB 2020 Redox priming promotes Aurora A activation during mitosis. Sci Signal 13:eabb6707.
39. Lowe J, Blanchard A, Morrell K, Lennox G, Reynolds L, Billett M, Landon M, Mayer RJ 1988 Ubiquitin is a common factor in intermediate filament inclusion bodies of diverse type in man, including those of Parkinson's disease, Pick's disease, and Alzheimer's disease, as well as Rosenthal fibres in cerebellar astrocytomas, cytoplasmic bodies in muscle, and mallory bodies in alcoholic liver disease. J Pathol 155:9–15.
40. Martinez A, Carmona M, Portero-Otin M, Naudi A, Pamplona R, Ferrer I 2008 Type-dependent oxidative damage in frontotemporal lobar degeneration:cortical astrocytes are targets of oxidative damage. J Neuropathol Exp Neurol 67:1122–1136.
41. McBean GJ 2017 Cysteine, glutathione, and thiol redox balance in astrocytes. Antioxidants (Basel) 6:62.
42. Messing A, Head MW, Galles K, Galbreath EJ, Goldman JE, Brenner M 1998 Fatal encephalopathy with astrocyte inclusions in GFAP transgenic mice. Am J Pathol 152:391–398.
43. Messing A, LaPash Daniels CM, Hagemann TL 2010 Strategies for treatment in Alexander disease. Neurotherapeutics 7:507–515.
44. Messing A 2018a Alexander disease. Handb Clin Neurol 148:693–700.
45. Messing A 2018b Alexander disease:a guide for patients and families. San Rafael:Morgan &Claypool Publishers doi:10.4199/C00156ED1V01Y201708NGL010.
46. Moeton M, Stassen OM, Sluijs JA, van der Meer VW, Kluivers LJ, van Hoorn H, Schmidt T, Reits EA, van Strien ME, Hol E 2016 GFAP isoforms control intermediate filament network dynamics, cell morphology, and focal adhesions. Cell Mol Life Sci 73:4101–4120.
47. Muntane G, Dalfo E, Martinez A, Rey MJ, Avila J, Perez M, Portero M, Pamplona R, Ayala V, Ferrer I 2006 Glial fibrillary acidic protein is a major target of glycoxidative and lipoxidative damage in Pick's disease. J Neurochem 99:177–185.
48. Pekny M, Johansson CB, Eliasson C, Stakeberg J, Wallén A, Perlmann T, Lendahl U, Betsholtz C, Berthold CH, Frisén J 1999 Abnormal reaction to central nervous system injury in mice lacking glial fibrillary acidic protein and vimentin. J Cell Biol 145:503–514.
49. Pekny T, Faiz M, Wilhelmsson U, Curtis MA, Matej R, Skalli O, Pekny M 2014 Synemin is expressed in reactive astrocytes and Rosenthal fibers in Alexander disease. APMIS 122:76–80.
50. Pekny M, Pekna M, Messing A, Steinhauser C, Lee JM, Parpura V, Hol EM, Sofroniew MV, Verkhratsky A 2016 Astrocytes:a central element in neurological diseases. Acta Neuropathol 131:323–345.
51. Ridge KM, Eriksson JE, Pekny M, Goldman RD 2022 Roles of vimentin in health and disease. Genes Dev 36:391–407.
52. Rodriguez-Rodriguez A, Egea-Guerrero JJ, Murillo-Cabezas F, Carrillo-Vico A 2014 Oxidative stress in traumatic brain injury. Curr Med Chem 21:1201–1211.
53. Shrestha S, Katiyar S, Sanz-Rodriguez CE, Kemppinen NR, Kim HW, Kadirvelraj R, Panagos C, Keyhaninejad N, Colonna M, Chopra P, Byrne DP, Boons GJ, van der Knaap E, Eyers PA, Edison AS, Wood ZA, Kannan N 2020 A redox-active switch in fructosamine-3-kinases expands the regulatory repertoire of the protein kinase superfamily. Sci Signal 13:eaax6313.
54. Smith HL, Freeman OJ, Butcher AJ, Holmqvis S, Humoud I, Schatzl T, Hughes DT, Verity NC, Swinden DP, Hayes J, de Weerd L, Rowitch DH, Franklin RJM, Mallucci GR 2020 Astrocyte
unfolded protein response induces a specific reactivity state that causes non-cell-autonomous neuronal degeneration. Neuron 105:855–866.
55. Tang G, Xu Z, Goldman JE 2006 Synergistic effects of the SAPK/JNK and the proteasome pathway on glial fibrillary acidic protein (GFAP) accumulation in Alexander disease. J Biol Chem 281:38634–38643.
56. Tang G, Yue Z, Talloczy Z, Goldman JE 2008a Adaptive autophagy in Alexander disease-affected astrocytes. Autophagy 4:701–703.
57. Tang G, Yue Z, Talloczy Z, Hagemann T, Cho W, Messing A, Sulzer DL, Goldman JE 2008b Autophagy induced by Alexander disease-mutant GFAP accumulation is regulated by p38/MAPK and mTOR signaling pathways. Hum Mol Genet 17:1540–1555.
58. Tang G, Perng MD, Wilk S, Quinlan R, Goldman JE 2010 Oligomers of mutant glial fibrillary acidic protein (GFAP) inhibit the proteasome system in alexander disease astrocytes, and the small heat shock protein alphaB-crystallin reverses the inhibition. J Biol Chem 285:10527–10537.
59. Tian R, Gregor M, Wiche G, Goldman JE 2006 Plectin regulates the organization of glial fibrillary acidic protein in Alexander disease. Am J Pathol 168:888–897.
60. Tian R, Wu X, Hagemann TL, Sosunov AA, Messing A, McKhann GM, Goldman JE 2010 Alexander disease mutant glial fibrillary acidic protein compromises glutamate transport in astrocytes. J Neuropathol Exp Neurol 69:335–345.
61. Truong TH, Carroll KS 2013 Redox regulation of protein kinases. Crit Rev Biochem Mol Biol 48:332–356.
62. van Asperen JV, Robe P, Hol EM 2022 GFAP alternative splicing and the relevance for disease - a focus on diffuse gliomas. ASN Neuro 14:17590914221102065.
63. Viedma-Poyatos A, de Pablo Y, Pekny M, Perez-Sala D 2018 The cysteine residue of glial fibrillary acidic protein is a critical target for lipoxidation and required for efficient network organization. Free Radic Biol Med 120:380–394.
64. Viedma-Poyatos A, Pajares MA, Perez-Sala D 2020 Type III intermediate filaments as targets and effectors of electrophiles and oxidants. Redox Biol 36:101582.
65. Viedma-Poyatos A, Gonzalez-Jimenez P, Pajares MA, Perez-Sala D 2022 Alexander disease GFAP R239C mutant shows increased susceptibility to lipoxidation and elicits mitochondrial dysfunction and oxidative stress. Redox Biol 55:102415.
66. Wang L, Hagemann TL, Kalwa, H, Michel T, Messing A, Feany MB 2015 Nitric oxide mediates glial-induced neurodegeneration in Alexander disease. Nat Commun 6:8966.
67. Yang AW, Lin NH, Yeh TH, Snider N, Perng MD 2022 Effects of Alexander disease-associated mutations on the assembly and organization of GFAP intermediate filaments. Mol Biol Cell 33:ar69.
68. Zang L, Wang J, Jiang Y, Gu Q, Gao Z, Yang Y, Xiao J, Wu Y 2013 Follow-up study of 22 Chinese children with Alexander disease and analysis of parental origin of de novo GFAP mutations. J Hum Genet 58:183–188.
