The dynactin p150 subunit: cell biology studies of sequence changes found in ALS/MND and Parkinsonian Syndromes

Stockmann, Marianne; Meyer-Ohlendorf, Marie; Achberger, Kevin; Putz, Stefan; Demestre, Maria; Yin, Haishan; Hendrich, Corinna; Linta, Leonhard; Heinrich, Jutta; Brunner, Cornelia; Proepper, Christian; Kuh, Georges Ful; Baumann, Bernd; Langer, Torben; Schwalenstöcker, Birgit; Braunstein, Kerstin E.; Arnim, Christine von; Schneuwly, Stephan; Meyer, Thomas; Wong, Philip C.; Boeckers, Tobias M.; Ludolph, Albert C.; Liebau, Stefan

doi:10.1007/s00702-012-0910-z

Cited by 32 publications

(33 citation statements)

References 33 publications

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“…Moreover, Stockmann et al identified 24 exonic variants among more than 2,700 mixed samples comprised of 1,708 sporadic ALS, 218 striatal diseases (multiple system atrophy, PSP, and HD), and 778 healthy controls. However, none of them had confirmed segregation in affected family members, and some of them were found in both the disease and control groups [52]. Therefore, with the exception of the p.Gly59Ser mutation seen in the HMN7B family, the pathogenicity of these DCTN1 variants identified in non-PS phenotypes remains to be established.…”

Section: Dctn1 Mutations/polymorphisms Associated With Other Phenotmentioning

confidence: 99%

“…However, functional analyses of the ALS-associated mutant p150 Glued (p.Met571Thr, p.Arg785Trp, p.Arg1101Lys, and p.Thr1249Ile) did not show any deficits. Microtubule binding abilities were preserved in all these mutations, and no aggregations were observed in the mutant-overexpressed culture cells [52, 64]. …”

Section: The Relevance Of Dctn1 Mutations To Neurodegenerationmentioning

confidence: 99%

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DCTN1-related neurodegeneration: Perry syndrome and beyond

Konno

Ross

Teive

et al. 2017

Parkinsonism & Related Disorders

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Perry syndrome (PS) is a rare hereditary neurodegenerative disease characterized by autosomal dominant parkinsonism, psychiatric symptoms, weight loss, central hypoventilation, and distinct TDP-43 pathology. The mutated causative gene for PS is DCTN1, which encodes the dynactin subunit p150Glued. Dynactin is a motor protein involved in axonal transport; the p150Glued subunit has a critical role in the overall function. Since the discovery of DCTN1 in PS, it has been increasingly recognized that DCTN1 mutations can exhibit more diverse phenotypes than previously thought. Progressive supranuclear palsy- and/or frontotemporal dementia-like phenotypes have been associated with the PS phenotypes. In addition, DCTN1 mutations were identified in a family with motor-neuron disease before the discovery in PS. In this review, we analyze the clinical and genetic aspects of DCTN1-related neurodegeneration and discuss its pathogenesis. We also describe three families with PS, Canadian, Polish, and Brazilian. DCTN1 mutation was newly identified in two of them, the Canadian and Polish families. The Canadian family was first described in late 1970’s but was never genetically tested. We recently had the opportunity to evaluate this family and to test the gene status of an affected family member. The Polish family is newly identified and is the first PS family in Poland. Although still rare, DCTN1-related neurodegeneration needs to be considered in a differential diagnosis of parkinsonian disorders, frontotemporal dementia, and motor-neuron diseases, especially if there is family history.

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Section: Dctn1 Mutations/polymorphisms Associated With Other Phenotmentioning

confidence: 99%

Section: The Relevance Of Dctn1 Mutations To Neurodegenerationmentioning

confidence: 99%

DCTN1-related neurodegeneration: Perry syndrome and beyond

Konno

Ross

Teive

et al. 2017

Parkinsonism & Related Disorders

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“…For example, p150 mutants found in patients impact the subcellular localization of p150 in motoneurons [Stockmann et al, 2013]. However, mutations within the microtubule-binding domain of p150…”

Section: Introductionmentioning

confidence: 99%

Cell Cycle‐Dependent Localization of Dynactin Subunit p150^glued at Centrosome

Chen

Syu

Han

et al. 2015

J of Cellular Biochemistry

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p150(glued) is the largest subunit of dynactin protein complex, through which cargo vesicles link to the microtubule minus-end directed motor protein dynein. In addition, p150(glued) also locates in the mother centriole where it organizes the subdistal appendage. The components of appendage are dynamically regulated throughout the cell cycle stages, but it is still unclear whether the centrosomal residency of p150(glued) correlated with cell cycle progression. Here we found that p150(glued) was located in the mother centriole during G1/S stage and its centrosomal residency was independent of microtubule transportation. However, the centrosomal p150(glued) became blurred at G2/M phase and this event was not regulated by its phosphorylation. Entering into mitosis, p150(glued) was robustly enriched in the mitotic spindle nearby the spindle poles but not in the centrosome. During serum starvation (G0 stage), p150(glued) appeared at the base of primary cilium and its depletion attenuated starvation-induced primary cilium formation. We also checked its role in the maintenance of centrosome homeostasis and configuration, and found depletion of p150(glued) did not induce centrosome amplification or splitting but inhibited U2OS cell growth. G1 arrest and reduced EdU incorporation were observed in p150(glued) deficient U2OS cells. In addition, cyclin E was downregulated following p150(glued) depletion. The p53/p21 signaling was activated indicating that CDKs were inactivated. The reduced cell growth was ameliorated in the p150(glued) depleted cells when treated with p53 inhibitor. Thus, we have identified the centrosomal targeting of p150(glued) in distinct cell cycle stage and uncovered its role in controlling G1/S transition.

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“…This is also reflected in the zebrafish dync1h1 (cannonball) mutant, which displays abnormal organelle positioning and accumulation of Golgi-associated vesicles in the inner segment of the retina (Insinna et al, 2010) and Schwann cell deficient myelination (Langworthy and Appel, 2012), a symptom common to NDDs. Additionally, dynactin mutations have been found in patients with amyotrophic lateral sclerosis and Perry syndrome (Stockmann et al, 2013). Death of sensory neurons and axonal degeneration is also reported in zebrafish with morpholino knockdown of dctn1a, dctn1b and dctn2a (Insinna et al, 2010) and the mutants dctn1a (mikre oko) (Tsujikawa et al, 2007) and dctn2 (ale oko) (Jing and Malicki, 2009).…”

Section: Zebrafish Tools To Study Microtubulesmentioning

confidence: 96%

In vivo cell biology in zebrafish – providing insights into vertebrate development and disease

Vacaru

Ünlü

Spitzner

et al. 2014

Journal of Cell Science

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Over the past decades, studies using zebrafish have significantly advanced our understanding of the cellular basis for development and human diseases. Zebrafish have rapidly developing transparent embryos that allow comprehensive imaging of embryogenesis combined with powerful genetic approaches. However, forward genetic screens in zebrafish have generated unanticipated findings that are mirrored by human genetic studies: disruption of genes implicated in basic cellular processes, such as protein secretion or cytoskeletal dynamics, causes discrete developmental or disease phenotypes. This is surprising because many processes that were assumed to be fundamental to the function and survival of all cell types appear instead to be regulated by cell-specific mechanisms. Such discoveries are facilitated by experiments in whole animals, where zebrafish provides an ideal model for visualization and manipulation of organelles and cellular processes in a live vertebrate. Here, we review well-characterized mutants and newly developed tools that underscore this notion. We focus on the secretory pathway and microtubule-based trafficking as illustrative examples of how studying cell biology in vivo using zebrafish has broadened our understanding of the role fundamental cellular processes play in embryogenesis and disease.

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The dynactin p150 subunit: cell biology studies of sequence changes found in ALS/MND and Parkinsonian Syndromes

Cited by 32 publications

References 33 publications

DCTN1-related neurodegeneration: Perry syndrome and beyond

DCTN1-related neurodegeneration: Perry syndrome and beyond

Cell Cycle‐Dependent Localization of Dynactin Subunit p150^glued at Centrosome

In vivo cell biology in zebrafish – providing insights into vertebrate development and disease

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The dynactin p150 subunit: cell biology studies of sequence changes found in ALS/MND and Parkinsonian Syndromes

Cited by 32 publications

References 33 publications

DCTN1-related neurodegeneration: Perry syndrome and beyond

DCTN1-related neurodegeneration: Perry syndrome and beyond

Cell Cycle‐Dependent Localization of Dynactin Subunit p150glued at Centrosome

In vivo cell biology in zebrafish – providing insights into vertebrate development and disease

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Cell Cycle‐Dependent Localization of Dynactin Subunit p150^glued at Centrosome