The role of gigaxonin in the degradation of the glial-specific intermediate filament protein GFAP

Lin, Ni Hsuan; Huang, Yu; Opal, Puneet; Goldman, Robert D.; Messing, Albee; Perng, Ming Der

doi:10.1091/mbc.e16-06-0362

Cited by 26 publications

(26 citation statements)

References 55 publications

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“…This effect is so robust that it also enables the clearance of vimentin bundles in fibroblasts from patients and GAN mouse embryonic fibroblasts (Mahammad et al, 2013). From this initial key findings, the potent effect of Gigaxonin has been extended to various IFs of the nervous system, and is now confirmed in normal cells [neurons in Mahammad et al (2013), Israeli et al (2016) and astrocytes in Lin et al (2016)], but also in disease context [GAN iPSC-derived neurons in Johnson-Kerner et al (2015a), and GAN DRG in Israeli et al (2016)]. To understand this unique action on multiple IFs proteins, that constitute the cytoskeleton of tissues throughout the body, it is important to introduce the structure of IF proteins.…”

Section: Gigaxonin Is a Universal Regulator Of The Intermediate Filammentioning

confidence: 86%

“…This interaction seems to be direct, as assessed by ELISA assay using recombinant vimentin proteins. Accordingly, additional studies showed that other IF types can be found in Gigaxonin immunocomplexes in HEK cells and astrocytes (Johnson-Kerner et al, 2015b;Lin et al, 2016). Interestingly, the potent action of Gigaxonin has been confirmed for keratin and GFAP, mutated and aggregating, respectively in the skin disease EBS and Alexander disease (Lin et al, 2016;Buchau et al, 2018).…”

Section: Gigaxonin Is a Universal Regulator Of The Intermediate Filammentioning

confidence: 93%

“…Accordingly, additional studies showed that other IF types can be found in Gigaxonin immunocomplexes in HEK cells and astrocytes (Johnson-Kerner et al, 2015b;Lin et al, 2016). Interestingly, the potent action of Gigaxonin has been confirmed for keratin and GFAP, mutated and aggregating, respectively in the skin disease EBS and Alexander disease (Lin et al, 2016;Buchau et al, 2018). Gigaxonin was shown to clear GFAP network in swi13 stably expressing various mutants but resistance was conferred to some GFAP mutants, which exhibit reduced binding capacity to Gigaxonin.…”

Section: Gigaxonin Is a Universal Regulator Of The Intermediate Filammentioning

confidence: 97%

“…While the interaction of Gigaxonin with IF proteins has been repeatedly confirmed, there was challenges in demonstrating its mode of action on IFs. Indeed, only a partial recovery of both vimentin and GFAP levels upon Gigaxonin overexpression was seen with proteasome inhibitor, and laddering of vimentin could not be evidenced with in vivo and in vitro assays, and very low with GFAP (Mahammad et al, 2013;Lin et al, 2016). One study was able to show a Gigaxonin-dependent ubiquitin laddering of peripherin in GAN DRG neurons (Israeli et al, 2016).…”

Section: Gigaxonin Is a Universal Regulator Of The Intermediate Filammentioning

confidence: 99%

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E3 Ubiquitin Ligases in Neurological Diseases: Focus on Gigaxonin and Autophagy

Lescouzères

Bomont

2020

Front. Physiol.

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Ubiquitination is a dynamic post-translational modification that regulates the fate of proteins and therefore modulates a myriad of cellular functions. At the last step of this sophisticated enzymatic cascade, E3 ubiquitin ligases selectively direct ubiquitin attachment to specific substrates. Altogether, the ∼800 distinct E3 ligases, combined to the exquisite variety of ubiquitin chains and types that can be formed at multiple sites on thousands of different substrates confer to ubiquitination versatility and infinite possibilities to control biological functions. E3 ubiquitin ligases have been shown to regulate behaviors of proteins, from their activation, trafficking, subcellular distribution, interaction with other proteins, to their final degradation. Largely known for tagging proteins for their degradation by the proteasome, E3 ligases also direct ubiquitinated proteins and more largely cellular content (organelles, ribosomes, etc.) to destruction by autophagy. This multi-step machinery involves the creation of double membrane autophagosomes in which engulfed material is degraded after fusion with lysosomes. Cooperating in sustaining homeostasis, actors of ubiquitination, proteasome and autophagy pathways are impaired or mutated in wide range of human diseases. From initial discovery of pathogenic mutations in the E3 ligase encoding for E6-AP in Angelman syndrome and Parkin in juvenile forms of Parkinson disease, the number of E3 ligases identified as causal gene for neurological diseases has considerably increased within the last years. In this review, we provide an overview of these diseases, by classifying the E3 ubiquitin ligase types and categorizing the neurological signs. We focus on the Gigaxonin-E3 ligase, mutated in giant axonal neuropathy and present a comprehensive analysis of the spectrum of mutations and the recent biological models that permitted to uncover novel mechanisms of action. Then, we discuss the common functions shared by Gigaxonin and the other E3 ligases in cytoskeleton architecture, cell signaling and autophagy. In particular, we emphasize their pivotal roles in controlling multiple steps of the autophagy pathway. In light of the various targets and extending functions sustained by a single E3 ligase, we finally discuss the challenge in understanding the complex pathological cascade underlying disease and in designing therapeutic approaches that can apprehend this complexity.

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Section: Gigaxonin Is a Universal Regulator Of The Intermediate Filammentioning

confidence: 86%

Section: Gigaxonin Is a Universal Regulator Of The Intermediate Filammentioning

confidence: 93%

Section: Gigaxonin Is a Universal Regulator Of The Intermediate Filammentioning

confidence: 97%

Section: Gigaxonin Is a Universal Regulator Of The Intermediate Filammentioning

confidence: 99%

See 2 more Smart Citations

E3 Ubiquitin Ligases in Neurological Diseases: Focus on Gigaxonin and Autophagy

Lescouzères

Bomont

2020

Front. Physiol.

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“…At 48 hours after transfection, cells were processed for immunofluorescence microscopy as described previously [32]. The primary antibodies used in this study were listed in Table 1.…”

Section: Methodsmentioning

confidence: 99%

Characterization of a panel of monoclonal antibodies recognizing specific epitopes on GFAP

2017

Self Cite

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Alexander disease (AxD) is a neurodegenerative disease caused by heterozygous mutations in the GFAP gene, which encodes the major intermediate filament protein of astrocytes. This disease is characterized by the accumulation of cytoplasmic protein aggregates, known as Rosenthal fibers. Antibodies specific to GFAP could provide invaluable tools to facilitate studies of the normal biology of GFAP and to elucidate the pathologic role of this IF protein in disease. While a large number of antibodies to GFAP are available, few if any of them have defined epitopes. Here we described the characterization of a panel of commonly used anti-GFAP antibodies, which recognized epitopes at regions extending across the rod domain of GFAP. We show that all of the antibodies are useful for immunoblotting and immunostaining, and identify a subset that preferentially recognized human GFAP. Using these antibodies, we demonstrate the presence of biochemically modified forms of GFAP in brains of human AxD patients and mouse AxD models. These data suggest that this panel of anti-GFAP antibodies will be useful for studies of animal and cell-based models of AxD and related diseases in which cytoskeletal defects associated with GFAP modifications occur.

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