DYT1 Dystonia Patient-Derived Fibroblasts Have Increased Deformability and Susceptibility to Damage by Mechanical Forces

Gill, Navjot Kaur; Ly, Chau; Kim, Paul H.; Saunders, Cosmo A.; Fong, Loren G.; Young, Stephen G.; Luxton, G. W. Gant; Rowat, Amy C.

doi:10.3389/fcell.2019.00103

Cited by 14 publications

(13 citation statements)

References 134 publications

(250 reference statements)

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“…We believe that this study provided a path to unravel candidate genome variants as modifiers. Our findings not only echo the previous research highlighting the defect of mechanosensing and mechanotransduction regulated by TOR1A (Gill et al, 2019), but provide knowledge for further understanding the disease origin of the DYT1 dystonia as well. We will recommend the physicians to test these variants once the TOR1A ΔE mutation patient show normal alleles within other TOR1A locus and other major binding proteins in their study.…”

Section: Discussionsupporting

confidence: 89%

“…This hypothesis is supported by the finding that torsinA loss elevates LINC complex levels in the mouse brain, which impairs brain morphogenesis (Dominguez Gonzalez et al, 2018). More recently, fibroblasts isolated from DYT1 dystonia patients were shown to have increased deformability similar to that of fibroblasts harvested from mice lacking the two major SUN proteins SUN1 and SUN2 (Gill et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…DYT1 dystonia patient-derived fibroblasts were also shown to have increased susceptibility to damage by mechanical forces (Gill et al, 2019) strongly suggests that cellular mechanics may impact the pathogenesis and/or pathophysiology of DYT1 dystonia. All cells, including neurons, adapt their mechanical properties by converting extracellular mechanical stimuli into biochemical signals and altered gene expression through the process of mechanotransduction (Barnes, Przybyla, & Weaver, 2017; Franze, 2013).…”

Section: Discussionmentioning

confidence: 99%

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Whole exome sequencing identifies novel DYT1 dystonia-associated genome variants as potential disease modifiers

Hu¹,

Luxton²,

Lee³

et al. 2020

Preprint

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AbstractBackgroundDYT1 dystonia is a neurological movement disorder characterized by painful sustained muscle contractions resulting in abnormal twisting and postures. In a subset of patients, it is caused by a loss-of-function mutation (ΔE302/303; or ΔE) in the luminal ATPases associated with various cellular activities (AAA+) protein torsinA encoded by the TOR1A gene. The low penetrance of the ΔE mutation (∼30-40%) suggests the existence of unknown genetic modifiers of DYT1 dystonia.MethodsTo identify these modifiers, we performed whole exome sequencing of blood leukocyte DNA isolated from two DYT1 dystonia patients, three asymptomatic carriers of the ΔE mutation, and an unaffected adult relative.ResultsA total of 264 DYT1 dystonia-associated variants (DYT1 variants) were identified in 195 genes. Consistent with the emerging view of torsinA as an important regulator of the cytoskeleton, endoplasmic reticulum homeostasis, and lipid metabolism, we found DYT1 variants in genes that encode proteins implicated in these processes. Moreover, 40 DYT1 variants were detected in 32 genes associated with neuromuscular and neuropsychiatric disorders.ConclusionThe DYT1 variants described in this work represent exciting new targets for future studies designed to increase our understanding of the pathophysiology and pathogenesis of DYT1 dystonia.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Whole exome sequencing identifies novel DYT1 dystonia-associated genome variants as potential disease modifiers

Hu¹,

Luxton²,

Lee³

et al. 2020

Preprint

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“…However, many distinct properties of Torsins produce a complicated system that has been reported to affect an ever-expanding number of cellular processes (Figure 1). Some of these diverse processes include lipid metabolism [21][22][23], nucleo-cytoskeleton coupling [24][25][26], membrane remodeling [13,27,28], ER redox monitoring [7,29], nuclear pore complex (NPC) biogenesis [30][31][32], and protein quality control [33][34][35][36][37] (Figure 1). In this review, we discuss recent findings that support roles for Torsins in NPC biogenesis and lipid metabolism and speculate how its AAA+ properties may relate to these processes.…”

Section: Figure 2 (A)mentioning

confidence: 99%

The Role of Torsin AAA+ Proteins in Preserving Nuclear Envelope Integrity and Safeguarding Against Disease

2020

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Torsin ATPases are members of the AAA+ (ATPases associated with various cellular activities) superfamily of proteins, which participate in essential cellular processes. While AAA+ proteins are ubiquitously expressed and demonstrate distinct subcellular localizations, Torsins are the only AAA+ to reside within the nuclear envelope (NE) and endoplasmic reticulum (ER) network. Moreover, due to the absence of integral catalytic features, Torsins require the NE- and ER-specific regulatory cofactors, lamina-associated polypeptide 1 (LAP1) and luminal domain like LAP1 (LULL1), to efficiently trigger their atypical mode of ATP hydrolysis. Despite their implication in an ever-growing list of diverse processes, the specific contributions of Torsin/cofactor assemblies in maintaining normal cellular physiology remain largely enigmatic. Resolving gaps in the functional and mechanistic principles of Torsins and their cofactors are of considerable medical importance, as aberrant Torsin behavior is the principal cause of the movement disorder DYT1 early-onset dystonia. In this review, we examine recent findings regarding the phenotypic consequences of compromised Torsin and cofactor activities. In particular, we focus on the molecular features underlying NE defects and the contributions of Torsins to nuclear pore complex biogenesis, as well as the growing implications of Torsins in cellular lipid metabolism. Additionally, we discuss how understanding Torsins may facilitate the study of essential but poorly understood processes at the NE and ER, and aid in the development of therapeutic strategies for dystonia.

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“…To date, the molecular mechanism underlying the contribution of TorA and TorB to herpesvirus nuclear egress as well as interphase NPC biogenesis remains poorly defined. Nevertheless, a growing body of evidence supports the hypothesis that TorA is required for the assembly of functional linker of nucleoskeleton and cytoskeleton (LINC) complexes [39,48,[56][57][58][59]. This conserved NE-spanning molecular bridge is present in all nucleated cells [60,61] and mechanically integrates the nucleus with the cytoskeleton mediating several fundamental cellular processes including cell division, DNA damage repair, meiotic chromosome pairing, mechano-regulation of gene expression, and nuclear positioning (reviewed in Meinke and Schirmer [62]).…”

Section: Introductionmentioning

confidence: 99%

Function of Torsin AAA+ ATPases in Pseudorabies Virus Nuclear Egress

Hölper

Klupp

Luxton

et al. 2020

Cells

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Newly assembled herpesvirus nucleocapsids traverse the intact nuclear envelope by a vesicle-mediated nucleo-cytoplasmic transport for final virion maturation in the cytoplasm. For this, they bud at the inner nuclear membrane resulting in primary enveloped particles in the perinuclear space (PNS) followed by fusion of the primary envelope with the outer nuclear membrane (ONM). While the conserved viral nuclear egress complex orchestrates the first steps, effectors of fusion of the primary virion envelope with the ONM are still mostly enigmatic but might include cellular proteins like SUN2 or ESCRT-III components. Here, we analyzed the influence of the only known AAA+ ATPases located in the endoplasmic reticulum and the PNS, the Torsins (Tor), on nuclear egress of the alphaherpesvirus pseudorabies virus. For this overexpression of wild type and mutant proteins as well as CRISPR/Cas9 genome editing was applied. Neither single overexpression nor gene knockout (KO) of TorA or TorB had a significant impact. However, TorA/B double KO cells showed decreased viral titers at early time points of infection and an accumulation of primary virions in the PNS pointing to a delay in capsid release during nuclear egress.Cells 2020, 9, 738 2 of 19 genome at early stages of infection. Traffic into and out of the nucleus is thought to occur exclusively through NPCs (reviewed in Adam [3], Knockenhauer and Schwartz [4]). Interestingly, herpesvirus nucleocapsids are translocated through the nuclear envelope (NE) by a vesicle-mediated process designated as nuclear egress (reviewed in [5][6][7]).Budding of herpesvirus nucleocapsids at the INM is driven by the nuclear egress complex (NEC) composed of two conserved herpesviral proteins designated as pUL31 and pUL34 in the alphaherpesviruses pseudorabies virus (PrV) and herpes simplex viruses (HSV-1, -2) [5][6][7]. The NEC is not only required for efficient nuclear egress, thereby generating primary enveloped virions in the PNS, but also sufficient for vesicle formation and scission from artificial lipid membranes and the INM, [8][9][10][11]. In a subsequent step, this primary envelope fuses with the ONM to release the nucleocapsids into the cytoplasm (reviewed in [12]).Budding of nucleocapsids at the INM is quite well understood at the molecular level, while the fusion process of the primary envelope with the ONM remains mostly enigmatic. In contrast to reports for HSV-1 [13], the viral fusion machinery which is active during entry of herpesviruses is not involved in nuclear egress of PrV [14]. In addition, a variety of different PrV gene deletion mutants studied so far showed no detectable effect on nuclear egress arguing against a virus-encoded fusion machinery active at the NE. Only mutants lacking the alphaherpesvirus specific protein kinase pUS3 showed an impairment of nuclear translocation. In the absence of pUS3 [15][16][17] or by impairment of its kinase function [18][19][20] primary enveloped virions accumulate in herniations of the INM. However, pUS3 is not essential for viral re...

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DYT1 Dystonia Patient-Derived Fibroblasts Have Increased Deformability and Susceptibility to Damage by Mechanical Forces

Cited by 14 publications

References 134 publications

Whole exome sequencing identifies novel DYT1 dystonia-associated genome variants as potential disease modifiers

Whole exome sequencing identifies novel DYT1 dystonia-associated genome variants as potential disease modifiers

The Role of Torsin AAA+ Proteins in Preserving Nuclear Envelope Integrity and Safeguarding Against Disease

Function of Torsin AAA+ ATPases in Pseudorabies Virus Nuclear Egress

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