Transgenic expression of neuronal dystonin isoform 2 partially rescues the disease phenotype of the dystonia musculorum mouse model of hereditary sensory autonomic neuropathy VI

Ferrier, Andrew; Sato, Tadasu; Repentigny, Yves De; Gibeault, Sabrina; Bhanot, Kunal; O’Meara, Ryan W.; Lynch-Godrei, Anisha; Kornfeld, Samantha F.; Young, Kevin G.; Kothary, Rashmi

doi:10.1093/hmg/ddt663

Cited by 31 publications

(31 citation statements)

References 38 publications

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“…Consistent with this, the hereditary and sensory autonomic neuropathy type VI in humans potentially associates with mutations in the human BPAG1 gene (Edvardson et al, 2012;Ferrier et al, 2014). Mutations in the major neurodegeneration-associated genes TAR DNA-binding protein (TARDBP), fused in sarcoma (FUS) and leucine-rich repeat kinase 2 (LRRK2) are associated with alternative splicing of BPAG1, which may be involved in development of neurodegeneration conditions such as Parkinson's disease (Elliott et al, 2012).…”

Section: Spectraplakins In Neuronal Degeneration and Parkinson's Diseasementioning

confidence: 96%

Spectraplakin family proteins – cytoskeletal crosslinkers with versatile roles

Zhang

Yue

2017

Journal of Cell Science

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The different cytoskeletal networks in a cell are responsible for many fundamental cellular processes. Current studies have shown that spectraplakins, cytoskeletal crosslinkers that combine features of both the spectrin and plakin families of crosslinkers, have a critical role in integrating these different cytoskeletal networks. Spectraplakin genes give rise to a variety of isoforms that have distinct functions. Importantly, all spectraplakin isoforms are uniquely able to associate with all three elements of the cytoskeleton, namely, F-actin, microtubules and intermediate filaments. In this Review, we will highlight recent studies that have unraveled their function in a wide range of different processes, from regulating cell adhesion in skin keratinocytes to neuronal cell migration. Taken together, this work has revealed a diverse and indispensable role for orchestrating the function of different cytoskeletal elements in vivo.

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Section: Spectraplakins In Neuronal Degeneration and Parkinson's Diseasementioning

confidence: 96%

Spectraplakin family proteins – cytoskeletal crosslinkers with versatile roles

Zhang

Yue

2017

Journal of Cell Science

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Section: Restoring Dst-a2 Expression In Dst Dt-tg4 Sensory Neurons Ammentioning

confidence: 99%

“…24,34,35 To determine if loss of DST-A2 underlies the autophagic defects observed in Dst dt-Tg4 sensory neurons, we employed the PrP-Dst-A2/PrPDst-A2;Dst dt-Tg4 transgenic mouse model. 34 These transgenic mice express exogenous DST-A2 under the control of the neuronal prion protein promoter (PrP-Dst-A2) on the Dst dt-Tg4 background. They robustly express DST-A2 throughout the nervous system, and particularly in sensory neurons, 34 and would be expected to exhibit a restoration or "rescue" of responses toward the WT phenotype.…”

Section: Restoring Dst-a2 Expression In Dst Dt-tg4 Sensory Neurons Ammentioning

confidence: 99%

“…34 These transgenic mice express exogenous DST-A2 under the control of the neuronal prion protein promoter (PrP-Dst-A2) on the Dst dt-Tg4 background. They robustly express DST-A2 throughout the nervous system, and particularly in sensory neurons, 34 and would be expected to exhibit a restoration or "rescue" of responses toward the WT phenotype. For simplicity, these mice will henceforth be termed PrP/Dst dt-Tg4 in the manuscript.…”

Section: Restoring Dst-a2 Expression In Dst Dt-tg4 Sensory Neurons Ammentioning

confidence: 99%

“…transgenic lines and characterization of mutations were described previously. 5,34,50 The onset of symptoms was generally assessed by the appearance of clasping of hind limbs after the mice were picked up by the tails. Dst dt-27J and Dst dt-Tg4 mice were genotyped by polymerase chain reaction (PCR) amplification of genomic tail DNA as previously described.…”

Section: Ethics Statementmentioning

confidence: 99%

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Disruption in the autophagic process underlies the sensory neuropathy indystonia musculorummice

et al. 2015

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#These authors contributed equally to this work.Keywords: autophagosome, BPAG1, DMC, dynein, dystonin, HSAN-VI, MAP1B, microtubules, traffickingAbbreviations: ANOVA, analysis of variance; CASP3, caspase 3, apoptosis-related cysteine peptidase; DRG, dorsal root ganglion; DST, dystonin; Dst dt , dystonia musculorum; DMEM, Dulbecco's modified Eagle's medium; DNAIC1, dynein, axonemal, intermediate chain 1; DMC, dynein/dynactin motor complex; EM, electron microscopy; FBS, fetal bovine serum; HSAN-VI, hereditary sensory and autonomic neuropathy type VI; MAP1LC3/LC3, microtubule associated-protein 1 light chain 3; MACF1, microtubuleactin crosslinking factor 1; MAP1B, microtubule-associated protein 1B; MT, microtubule; P, postnatal day; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; PrP, prion protein; RT-PCR, reverse transcription-polymerase chain reaction; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; SQTSM1/p62, sequestosome 1; TCA, trichloroacetic acid; TUBB3, tubulin, b, 3 class III; WT, wild type A homozygous mutation in the DST (dystonin) gene causes a newly identified lethal form of hereditary sensory and autonomic neuropathy in humans (HSAN-VI). DST loss of function similarly leads to sensory neuron degeneration and severe ataxia in dystonia musculorum (Dst dt ) mice. DST is involved in maintaining cytoskeletal integrity and intracellular transport. As autophagy is highly reliant upon stable microtubules and motor proteins, we assessed the influence of DST loss of function on autophagy using the Dst dt-Tg4 mouse model. Electron microscopy (EM) revealed an accumulation of autophagosomes in sensory neurons from these mice. Furthermore, we demonstrated that the autophagic flux was impaired. Levels of LC3-II, a marker of autophagosomes, were elevated. Consequently, Dst dt-Tg4 sensory neurons displayed impaired protein turnover of autophagosome substrate SQTSM1/p62 and of polyubiquitinated proteins. Interestingly, in a previously described Dst dt-Tg4 mouse model that is partially rescued by neuronal specific expression of the DST-A2 isoform, autophagosomes, autolysosomes, and damaged organelles were reduced when compared to Dst dt-Tg4 mutant mice. LC3-II, SQTSM1, polyubiquitinated proteins and autophagic flux were also restored to wild-type levels in the rescued mice. Finally, a significant decrease in DNAIC1 (dynein, axonemal, intermediate chain 1; the mouse ortholog of human DNAI1), a member of the DMC (dynein/dynactin motor complex), was noted in Dst dt-Tg4 dorsal root ganglia and sensory neurons. Thus, DST-A2 loss of function perturbs late stages of autophagy, and dysfunctional autophagy at least partially underlies Dst dt pathogenesis. We therefore conclude that the DST-A2 isoform normally facilitates autophagy within sensory neurons to maintain cellular homeostasis.

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Role of Plakins in Human Genetic Disease

Favre

Borradori

2016

Encyclopedia of Life Sciences

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The mammalian plakins comprise a small family of seven large proteins: bullous pemphigoid antigen 1, desmoplakin, envoplakin, epiplakin, microtubule‐actin crosslinking factor 1, periplakin and plectin. Their main functions consist of organising the different components of the cytoskeleton, crosslinking them to each other and anchoring them to various cell–matrix and cell–cell adhesion complexes. Thereby, these cytolinkers regulate cell stiffness, adhesion, migration and polarisation in a dynamic way. They can also interact with signal transducers, serve as scaffolds for signalling complexes and modulate vesicle trafficking. Congenital or engineered mutations in human and mouse plakin genes, respectively, reveal their essential functions in tissues either subjected to mechanical stress, such as the skin, skeletal and cardiac muscle, or highly sensitive to cytoskeletal and vesicle transport disorganisation, the nervous system. The pleiotropic diseases caused by plakin mutations reflect their multiple functions that have not yet been fully elucidated. Key Concepts The plakins are a family of cytolinker proteins that connect the three components of the cytoskeleton, intermediate filaments (IFs), microfilaments and microtubules (MTs), to each other and to junctional complexes at the cell membrane. The plakin family can be subdivided into three classes: (1) the canonical IF‐anchoring plakins: BPAG1e, desmoplakin, envoplakin, periplakin and plectin, (2) the atypical IF‐interacting plakin: epiplakin and (3) the MT‐binding spectraplakins: BPAG1a/b and MACF1a/b. The plakins often have a dynamic function on the cytoskeleton organisation, can modulate cell signalling and serve as scaffolds for signal transducers. The plakins also play a role in the positioning and function of organelles and regulate vesicular trafficking. Mutations in plakin genes can cause pleiotropic diseases, such as skin blistering, muscular dystrophy, cardiomyopathy and autonomic neuropathy. Despite the delimitation of plakin subdomains and the present knowledge of plakin functions, there is no obvious genotype–phenotype relationship.

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Transgenic expression of neuronal dystonin isoform 2 partially rescues the disease phenotype of the dystonia musculorum mouse model of hereditary sensory autonomic neuropathy VI

Cited by 31 publications

References 38 publications

Spectraplakin family proteins – cytoskeletal crosslinkers with versatile roles

Spectraplakin family proteins – cytoskeletal crosslinkers with versatile roles

Disruption in the autophagic process underlies the sensory neuropathy indystonia musculorummice

Role of Plakins in Human Genetic Disease

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