Ataxin-3 Plays a Role in Mouse Myogenic Differentiation through Regulation of Integrin Subunit Levels

Costa, Maria do Carmo; Bajanca, Fernanda; Rodrigues, Ana João; Tomé, Ricardo J.; Corthals, Garry L.; Macedo-Ribeiro, Sandra; Paulson, Henry L.; Logarinho, Elsa; Maciel, Patrı́cia

doi:10.1371/journal.pone.0011728

Cited by 23 publications

(9 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In terms of DUBs and myofibroblasts, a recent study demonstrated that the DUB UCHL1 is significantly induced during stellate cell activation, and knockdown of UCHL1 blocks progression of CCl 4 -induced fibrosis in mice (Wilson et al, 2015). In terms of DUBs and integrins, one group demonstrated that the DUB ataxin-3 regulates integrin α5 and the dysregulation of α5 by ataxin-3 is a critical component of the neurological disorder Machado-Joseph disease (do Carmo Costa et al, 2010). USP10 is also a DUB for several nonintegrin proteins and thus USP10 regulation is likely to be tissue-and context-specific.…”

Section: Discussionmentioning

confidence: 99%

The deubiquitylase USP10 regulates integrin β1 and β5 and fibrotic wound healing

Gillespie

Tedesco

Wang

et al. 2017

Journal of Cell Science

View full text Add to dashboard Cite

Scarring and fibrotic disease result from the persistence of myofibroblasts characterized by high surface expression of αv integrins and subsequent activation of the transforming growth factor β (TGFβ) proteins; however, the mechanism controlling their surface abundance is unknown. Genetic screening revealed that human primary stromal corneal myofibroblasts overexpress a subset of deubiquitylating enzymes (DUBs), which remove ubiquitin from proteins, preventing degradation. Silencing of the DUB USP10 induces a buildup of ubiquitin on integrins β1 and β5 in cell lysates, whereas recombinant USP10 removes ubiquitin from these integrin subunits. Correspondingly, the loss and gain of USP10 decreases and increases, respectively, αv/β1/β5 protein levels, without altering gene expression. Consequently, endogenous TGFβ is activated and the fibrotic markers alpha-smooth muscle actin (α-SMA) and cellular fibronectin (FN-EDA) are induced. Blocking either TGFβ signaling or cell-surface αv integrins after USP10 overexpression prevents or reduces fibrotic marker expression. Finally, silencing of USP10 in an cornea organ culture model prevents the induction of fibrotic markers and promotes regenerative healing. This novel mechanism puts DUB expression at the head of a cascade regulating integrin abundance and suggests USP10 as a novel antifibrotic target.

show abstract

Section: Discussionmentioning

confidence: 99%

The deubiquitylase USP10 regulates integrin β1 and β5 and fibrotic wound healing

Gillespie

Tedesco

Wang

et al. 2017

Journal of Cell Science

View full text Add to dashboard Cite

show abstract

“…In the specific case of myoblast differentiation into muscle fibers (myogenesis), ATXN3 is critical to the initial differentiation steps to organize the cytoskeleton and to regulate the levels of integrin subunits and other proteins involved in integrin-mediated signaling (do Carmo Costa et al , 2010). Because ATXN3 interacts with and stabilizes α5 integrin in a DUB activity-dependent manner, it most likely regulates the degradation of this protein through its role in ubiquitin-dependent proteostasis (do Carmo Costa et al , 2010). This basal function of ATXN3 may be common to many cell types.…”

Section: The Atxn3 Product Atxn3mentioning

confidence: 99%

“…In C.elegans and Drosophila models of MJD, mutant ATXN3 aggregates induce swelling and aberrant branching of neuronal processes, which impairs synaptic transmission (Gunawardena and Goldstein, 2005; Khan et al , 2006). ATXN3 interacts with cytoskeletal components and is important for cytoskeletal organization, thus it might normally play a role in cytoskeletal transport that becomes dysregulated in mutant ATXN3 (Burnett and Pittman, 2005; do Carmo Costa et al , 2010; Rodrigues et al , 2010). Insights from these studies suggest that axonal dysfunction may play a role in MJD pathogenesis and may explain why MJD patients often have motor neuropathy or neuronopathy.…”

Section: Mutant Atxn3 and Disease Pathogenesismentioning

confidence: 99%

Toward understanding Machado–Joseph disease

Costa

Paulson

2012

Progress in Neurobiology

Self Cite

229

236

View full text Add to dashboard Cite

Machado-Joseph disease (MJD), also known as Spinocerebellar ataxia type 3 (SCA3), is the most common inherited spinocerebellar ataxia and one of many polyglutamine neurodegenerative diseases. In MJD, a CAG repeat expansion encodes an abnormally long polyglutamine (polyQ) tract in the disease protein, ATXN3. Here we review MJD, focusing primarily on the function and dysfunction of ATXN3 and on advances toward potential therapies. ATXN3 is a deubiquitinating enzyme (DUB) whose highly specialized properties suggest that it participates in ubiquitin-dependent proteostasis. By virtue of its interactions with VCP, various ubiquitin ligases and other ubiquitin-linked proteins, ATXN3 may help regulate the stability or activity of many proteins in diverse cellular pathways implicated in proteotoxic stress response, aging, and cell differentiation. Expansion of the polyQ tract in ATXN3 is thought to promote an altered conformation in the protein, leading to changes in interactions with native partners and to the formation of insoluble aggregates. The development of a wide range of cellular and animal models of MJD has been crucial to the emerging understanding of ATXN3 dysfunction upon polyQ expansion. Despite many advances, however, the principal molecular mechanisms by which mutant ATXN3 elicits neurotoxicity remain elusive. In a chronic degenerative disease like MJD, it is conceivable that mutant ATXN3 triggers multiple, interconnected pathogenic cascades that precipitate cellular dysfunction and eventual cell death. A better understanding of these complex molecular mechanisms will be important as scientists and clinicians begin to focus on developing effective therapies for this incurable, fatal disorder.

show abstract

“…Machado-Joseph disease (MJD), or spinocerebellar ataxia type 3 (SCA3), is a neurodegenerative disorder caused by an expansion in the number of CAG repeats in the ATXN3/MJD1 gene resulting in an expanded polyglutamine tract in the ataxin-3 protein [51,63]. Although ataxin-3 functions are still poorly understood, this protein is known as a deubiquitinating enzyme involved in protein quality-control, particularly within the proteasome system, regulating the ubiquitinated status of many proteins; moreover, ataxin-3 is involved in transcription regulation, cytoskeleton organization and myogenesis [12,16,55,64].…”

Section: Introductionmentioning

confidence: 99%

The blood-brain barrier is disrupted in Machado-Joseph disease/spinocerebellar ataxia type 3: evidence from transgenic mice and human post-mortem samples

Lobo

Nobre

Miranda

et al. 2020

acta neuropathol commun

View full text Add to dashboard Cite

Blood-brain barrier (BBB) disruption is a common feature in neurodegenerative diseases. However, BBB integrity has not been assessed in spinocerebellar ataxias (SCAs) such as Machado-Joseph disease/SCA type 3 (MJD/SCA3), a genetic disorder, triggered by polyglutamine-expanded ataxin-3. To investigate that, BBB integrity was evaluated in a transgenic mouse model of MJD and in human post-mortem brain tissues. Firstly, we investigated the BBB permeability in MJD mice by: i) assessing the extravasation of the Evans blue (EB) dye and blood-borne proteins (e.g fibrinogen) in the cerebellum by immunofluorescence, and ii) in vivo Dynamic Contrast Enhanced-Magnetic Resonance Imaging (DCE-MRI). The presence of ataxin-3 aggregates in brain blood vessels and the levels of tight junction (TJ)-associated proteins were also explored by immunofluorescence and western blotting. Human brain samples were used to confirm BBB permeability by evaluating fibrinogen extravasation, co-localization of ataxin-3 aggregates with brain blood vessels and neuroinflammation. In the cerebellum of the mouse model of MJD, there was a 5-fold increase in EB accumulation when compared to age-matched controls. Moreover, vascular permeability displayed a 13-fold increase demonstrated by DCE-MRI. These results were validated by the 2-fold increase in fibrinogen extravasation in transgenic animals comparing to controls. Interestingly, mutant ataxin-3 aggregates were detected in cerebellar blood vessels of transgenic mice, accompanied by alterations of TJ-associated proteins in cerebellar endothelial cells, namely a 29% decrease in claudin-5 oligomers and a 10-fold increase in an occludin cleavage fragment. These results were validated in postmortem brain samples from MJD patients as we detected fibrinogen extravasation across BBB, the presence of ataxin-3 aggregates in blood vessels and associated microgliosis.

show abstract

Ataxin-3 Plays a Role in Mouse Myogenic Differentiation through Regulation of Integrin Subunit Levels

Cited by 23 publications

References 61 publications

The deubiquitylase USP10 regulates integrin β1 and β5 and fibrotic wound healing

The deubiquitylase USP10 regulates integrin β1 and β5 and fibrotic wound healing

Toward understanding Machado–Joseph disease

The blood-brain barrier is disrupted in Machado-Joseph disease/spinocerebellar ataxia type 3: evidence from transgenic mice and human post-mortem samples

Contact Info

Product

Resources

About