Behavioral defects in a DCTN1G71A transgenic mouse model of Perry syndrome

Mishima, Takayasu; Deshimaru, Manami; Watanabe, Takatomo; Kinoshita-Kawada, Mariko; Yuasa-Kawada, Junichi; Takasaki, Kotaro; Uehara, Yoshio; Jinno, Shozo; Iwasaki, Katsunori; Tsuboi, Yoshio

doi:10.1016/j.neulet.2017.12.038

Cited by 8 publications

(5 citation statements)

References 23 publications

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“…1 , 2 ). DCTN1 loss and disease-linked mutations in DCTN1 alone were previously shown to cause neuronal dysfunction and eventual neurodegeneration in cultured neurons [ 29 ], C. elegans [ 16 ], Drosophila [ 2 , 15 , 23 ], and mice [ 7 , 26 , 45 ]. Our data showing the appearance of abnormal small vacuole-like structures in the retina of DCTN1-IR flies (Fig.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of stress granule dynamics by DCTN1 deficiency exacerbates TDP-43 pathology in Drosophila models of ALS/FTD

Ueda,

Takeuchi,

Fujikake

et al. 2024

acta neuropathol commun

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The abnormal aggregation of TDP-43 into cytoplasmic inclusions in affected neurons is a major pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although TDP-43 is aberrantly accumulated in the neurons of most patients with sporadic ALS/FTD and other TDP-43 proteinopathies, how TDP-43 forms cytoplasmic aggregates remains unknown. In this study, we show that a deficiency in DCTN1, a subunit of the microtubule-associated motor protein complex dynactin, perturbs the dynamics of stress granules and drives the formation of TDP-43 cytoplasmic aggregation in cultured cells, leading to the exacerbation of TDP-43 pathology and neurodegeneration in vivo. We demonstrated using a Drosophila model of ALS/FTD that genetic knockdown of DCTN1 accelerates the formation of ubiquitin-positive cytoplasmic inclusions of TDP-43. Knockdown of components of other microtubule-associated motor protein complexes, including dynein and kinesin, also increased the formation of TDP-43 inclusions, indicating that intracellular transport along microtubules plays a key role in TDP-43 pathology. Notably, DCTN1 knockdown delayed the disassembly of stress granules in stressed cells, leading to an increase in the formation of pathological cytoplasmic inclusions of TDP-43. Our results indicate that a deficiency in DCTN1, as well as disruption of intracellular transport along microtubules, is a modifier that drives the formation of TDP-43 pathology through the dysregulation of stress granule dynamics.

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Section: Discussionmentioning

confidence: 99%

Dysregulation of stress granule dynamics by DCTN1 deficiency exacerbates TDP-43 pathology in Drosophila models of ALS/FTD

Ueda,

Takeuchi,

Fujikake

et al. 2024

acta neuropathol commun

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show abstract

“…Using biochemical analysis with a panel of truncated mutants, we also found that DCTN1 binds to TDP-43 and demonstrated that the DCTN1 CAP-Gly-basic supradomain, dynactin domain, and C-terminal region interacted with TDP-43, preferentially through its C-terminal region [81]. In mouse models, we have focused on the p.G71A mutation, which presents a typical Perry disease phenotype, and generated transgenic (Tg) and knock-in mice [82,83]. DCTN1 G71A transgenic mice showed behavioral defects, parallel apathy-like symptoms, and parkinsonism [82]; furthermore, these knockin mice displayed a decrease in TH immunoreactivity in the neurons of the substantia nigra [83].…”

Section: Basic Research Of Perry Diseasementioning

confidence: 99%

“…In mouse models, we have focused on the p.G71A mutation, which presents a typical Perry disease phenotype, and generated transgenic (Tg) and knock-in mice [82,83]. DCTN1 G71A transgenic mice showed behavioral defects, parallel apathy-like symptoms, and parkinsonism [82]; furthermore, these knockin mice displayed a decrease in TH immunoreactivity in the neurons of the substantia nigra [83]. Yu J et al generated DCTN1 conditional knockout mice by deleting DCTN1 in midbrain dopaminergic neurons [84,85].…”

Section: Basic Research Of Perry Diseasementioning

confidence: 99%

Perry Disease: Bench to Bedside Circulation and a Team Approach

Mishima,

Yuasa-Kawada,

Fujioka

et al. 2024

Biomedicines

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With technological applications, especially in genetic testing, new diseases have been discovered and new disease concepts have been proposed in recent years; however, the pathogenesis and treatment of these rare diseases are not as well established as those of common diseases. To demonstrate the importance of rare disease research, in this paper we focus on our research topic, Perry disease (Perry syndrome). Perry disease is a rare autosomal dominant neurodegenerative disorder clinically characterized by parkinsonism, depression/apathy, weight loss, and respiratory symptoms including central hypoventilation and central sleep apnea. The pathological classification of Perry disease falls under TAR DNA-binding protein 43 (TDP-43) proteinopathies. Patients with Perry disease exhibit DCTN1 mutations, which is the causative gene for the disease; they also show relatively uniform pathological and clinical features. This review summarizes recent findings regarding Perry disease from both basic and clinical perspectives. In addition, we describe technological innovations and outline future challenges and treatment prospects. We discuss the expansion of research from rare diseases to common diseases and the importance of collaboration between clinicians and researchers. Here, we highlight the importance of researching rare diseases as it contributes to a deeper understanding of more common diseases, thereby opening up new avenues for scientific exploration.

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“…The DCTN1 gene encodes p150 Glued , the largest subunit of the dynactin complex. p150 Glued is essential for cargo transport along microtubules, functioning with the dynein retrograde motor [60]. Eight point mutations have been identified: F52L, G71A, G67D, G71R, G71E, T72P, Q74P and Y78C in the DCTN1 gene [58].…”

Section: Cellular Modeling Of Pd and Atypical Parkinsonian Syndrommentioning

confidence: 99%

Modeling Parkinson’s Disease and Atypical Parkinsonian Syndromes Using Induced Pluripotent Stem Cells

Mishima

Fujioka

Fukae

et al. 2018

IJMS

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Parkinson’s disease (PD) and atypical parkinsonian syndromes are age-dependent multifactorial neurodegenerative diseases, which are clinically characterized by bradykinesia, tremor, muscle rigidity and postural instability. Although these diseases share several common clinical phenotypes, their pathophysiological aspects vary among the disease categories. Extensive animal-based approaches, as well as postmortem studies, have provided important insights into the disease mechanisms and potential therapeutic targets. However, the exact pathological mechanisms triggering such diseases still remain elusive. Furthermore, the effects of drugs observed in animal models are not always reproduced in human clinical trials. By using induced pluripotent stem cell (iPSC) technology, it has become possible to establish patient-specific iPSCs from their somatic cells and to effectively differentiate these iPSCs into different types of neurons, reproducing some key aspects of the disease phenotypes in vitro. In this review, we summarize recent findings from iPSC-based modeling of PD and several atypical parkinsonian syndromes including multiple system atrophy, frontotemporal dementia and parkinsonism linked to chromosome 17 and Perry syndrome. Furthermore, we discuss future challenges and prospects for modeling and understanding PD and atypical parkinsonian syndromes.

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Behavioral defects in a DCTN1G71A transgenic mouse model of Perry syndrome

Cited by 8 publications

References 23 publications

Dysregulation of stress granule dynamics by DCTN1 deficiency exacerbates TDP-43 pathology in Drosophila models of ALS/FTD

Dysregulation of stress granule dynamics by DCTN1 deficiency exacerbates TDP-43 pathology in Drosophila models of ALS/FTD

Perry Disease: Bench to Bedside Circulation and a Team Approach

Modeling Parkinson’s Disease and Atypical Parkinsonian Syndromes Using Induced Pluripotent Stem Cells

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