Dystonin/Bpag1 is a necessary endoplasmic reticulum/nuclear envelope protein in sensory neurons

Young, Kevin G.; Kothary, Rashmi

doi:10.1016/j.yexcr.2008.06.021

Cited by 44 publications

(66 citation statements)

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“…28,29 Furthermore, DST-A2 was also ascribed a role in sustaining and modifying endoplasmic reticulum morphology. 35,44 Collectively, the current experimental evidence supports DST-A2 as an important regulator of the endomembrane system 45 and therefore as a putative component of the autophagy pathway. Thus, the loss of both DST-A1 and DST-A2, such as in Dst dt-Tg4 mice, has severe consequences for autophagy.…”

Section: How Does Dst Affect Autophagy?supporting

confidence: 54%

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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Section: How Does Dst Affect Autophagy?supporting

confidence: 54%

Disruption in the autophagic process underlies the sensory neuropathy indystonia musculorummice

et al. 2015

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“…It is well known that loss-of-function mutations in Bpag1 in mice leads to a lethal movement disorder, dystonia musculorum, which is likely caused by degeneration of sensory neurons (Ferrier et al, 2013;Guo et al, 1995;Lynch-Godrei and Kothary, 2016;Yang et al, 1996;Young and Kothary, 2008). 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).…”

Section: Spectraplakins In Neuronal Degeneration and Parkinson's Diseasementioning

confidence: 76%

“…It has been shown that the BPAG1a2 isoform (also known as dystonin-a2) has a role as a mediator of normal ER structure and function. For example, BPAG1 mutant mice show defects at the ER in sensory neurons, which corresponds to the induction of ER-stress proteins (Young and Kothary, 2008). ER stress leads to sensory neurodegeneration through the induction of a proapoptotic caspase cascade (Nakagawa et al, 2000).…”

Section: Cellular Functions Of Bpag1mentioning

confidence: 99%

“…ER stress leads to sensory neurodegeneration through the induction of a proapoptotic caspase cascade (Nakagawa et al, 2000). BPAG1a2 potentially regulates the ER response by linking actin filaments with the ER membrane, which is critical for maintaining neuronal integrity (Young and Kothary, 2008). Moreover, BPAG1a2 associates with microfilaments that surround the nucleus and Golgi, and thus may also be involved in cytoskeletal organization and membrane attachment in the nuclear region (Young et al, 2006) (see Fig.…”

Section: Cellular Functions Of Bpag1mentioning

confidence: 99%

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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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“…Therefore, the ability to move the DTC nucleus is strongly dependent on VAB-10B1. Spectraplakins are also involved in the structuring, positioning and organization of organelles, including the nucleus, endoplasmic reticulum and mitochondria in other systems (Gupta et al, 2010;Roper and Brown, 2004;Young et al, 2003;Young et al, 2006;Young and Kothary, 2008). Because the MT outgrowth in the DTC front region has a clear polarity that directs the plus ends towards the nucleus, it is possible that MTs play roles in nuclear translocation of DTCs.…”

Section: Research Articlementioning

confidence: 99%

VAB-10 spectraplakin acts in cell and nuclear migration in Caenorhabditis elegans

et al. 2011

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SUMMARYCytoskeletal regulation is important in cell migration. The Caenorhabditis elegans gonadal distal tip cells (DTCs) offer a simple model with which to investigate the mechanism of cell migration in organogenesis. Here, we report that one of the spectraplakin isoforms, VAB-10B1, plays an essential role in cell and nuclear migration of DTCs by regulating the actin and microtubule (MT) cytoskeleton. In the vab-10(tk27) mutant, which lacks VAB-10B1, alignment of filamentous (F)-actin and MTs was weakly and severely disorganized, respectively, which resulted in a failure to translocate the DTC nucleus and a premature termination of DTC migration. An MT growing-tip marker, EBP-2-GFP, revealed that polarized outgrowth of MTs towards the nuclei of migrating DTCs was strikingly impaired in tk27 animals. A vab-10 mini-gene encoding only the actin-and MT-binding domains significantly rescued the gonadal defects, suggesting that VAB-10B1 has a role in linking actin and MT filaments. These results suggest that VAB-10B1/spectraplakin regulates the polarized alignment of MTs, possibly by linking F-actin and MTs, which enables normal nuclear translocation and cell migration of DTCs.

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Dystonin/Bpag1 is a necessary endoplasmic reticulum/nuclear envelope protein in sensory neurons

Cited by 44 publications

References 46 publications

Disruption in the autophagic process underlies the sensory neuropathy indystonia musculorummice

Disruption in the autophagic process underlies the sensory neuropathy indystonia musculorummice

Spectraplakin family proteins – cytoskeletal crosslinkers with versatile roles

VAB-10 spectraplakin acts in cell and nuclear migration in Caenorhabditis elegans

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