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Zbigniew K. Wszolek - One of the best experts on this subject based on the ideXlab platform.
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dctn1 related neurodegeneration Perry Syndrome and beyond
Parkinsonism & Related Disorders, 2017Co-Authors: Takuya Konno, Owen A Ross, Helio A G Teive, Jaroslaw Slawek, Dennis W Dickson, Zbigniew K. WszolekAbstract:Abstract 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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Perry Syndrome: A Distinctive Type of TDP-43 Proteinopathy.
Journal of Neuropathology and Experimental Neurology, 2017Co-Authors: Takayasu Mishima, Koji Kasanuki, Monica Castanedes-casey, Zbigniew K. Wszolek, Shin J Oh, Yoshio Tsuboi, Shunsuke Koga, Dennis W DicksonAbstract:Perry Syndrome is a rare atypical parkinsonism with depression, apathy, weight loss, and central hypoventilation caused by mutations in dynactin p150glued (DCTN1). A rare distal hereditary motor neuropathy, HMN7B, also has mutations in DCTN1. Perry Syndrome has TAR DNA-binding protein of 43 kDa (TDP-43) inclusions as a defining feature. Other TDP-43 proteinopathies include amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with and without motor neuron disease (FTLD-MND). TDP-43 forms aggregates in neuronal cytoplasmic inclusions (NCIs), neuronal intranuclear inclusions, dystrophic neurites (DNs), as well as axonal spheroids, oligodendroglial cytoplasmic inclusions, and perivascular astrocytic inclusions (PVIs). We performed semiquantitative assessment of these lesions and presence of dynactin subunit p50 lesions in 3 cases of Perry Syndrome and one of HMN7B. We compared them with 3 cases of FTLD-MND, 3 of ALS, and 3 of hippocampal sclerosis (HpScl). Perry Syndrome had NCIs, DNs, and frequent PVIs and spheroids. Perry Syndrome cases were similar, but different from ALS, FTLD-MND, and HpScl. TDP-43 pathology was not detected in HMN7B. Dynactin p50 inclusions were observed in both Perry Syndrome and HMN7B, but not in the other conditions. These results suggest that Perry Syndrome may be distinctive type of TDP-43 proteinopathy.
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Reduced orexin immunoreactivity in Perry Syndrome and multiple system atrophy.
Parkinsonism & related disorders, 2017Co-Authors: Takayasu Mishima, Koji Kasanuki, Monica Castanedes-casey, Zbigniew K. Wszolek, Yoshio Tsuboi, Shunsuke Koga, Dennis W DicksonAbstract:Abstract Introduction Orexin is a neuropeptide that plays a key role in maintaining a state of arousal, and possibly associates with sleep apnea Syndrome (SAS). Reduced orexin immunoreactivity has been reported in various neurologic conditions such as narcolepsy, Alzheimer’s disease, Lewy body disease and multiple system atrophy (MSA); however, there has been no report investigating orexin in Perry Syndrome, a rare hereditary neurodegenerative disease characterized by four clinical cardinal signs (parkinsonism, depression/apathy, weight loss, and central hypoventilation). Perry Syndrome patients frequently have sleep disturbances, including SAS and insomnia. Methods We evaluated orexin immunoreactivity in Perry Syndrome. Using imaging analysis, we quantitatively assessed orexin immunoreactivity in the nucleus basalis of Meynert in three Perry Syndrome cases, as well as five cases of frontotemporal lobar degeneration with motor neuron disease, five cases of MSA and five age-matched controls. For these cases, antemortem clinical information on sleep disturbances has been reviewed. Results In Perry Syndrome and MSA, there was reduction of orexin immunoreactivity compared with controls (Perry Syndrome: p = 0.020, MSA: p Conclusions This is the first report assessing orexin immunoreactivity in Perry Syndrome, and it showed significant reduction, similar to select neurodegenerative diseases, such as MSA. Further analysis with more cases will be needed to elucidate the specific mechanism of orexin loss in these disorders.
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in vivo dopaminergic and serotonergic dysfunction in dctn1 gene mutation carriers
Movement Disorders, 2014Co-Authors: Andre C Felicio, Katherine Dinelle, Jessamyn Mckenzie, Nicole Heffernan, Jeremy Road, Silke Appelcresswell, Matthew J Farrer, Zbigniew K. Wszolek, Pankaj Agarwal, Michael SchulzerAbstract:Introduction We used positron emission tomography (PET) to assess dopaminergic and serotonergic terminal density in three subjects carrying a mutation in the DCT1 gene, two clinically affected with Perry Syndrome. Methods All subjects had brain imaging using 18F-6-fluoro-l-dopa (FDOPA, dopamine synthesis and storage), (+)-11C-dihydrotetrabenazine (DTBZ, vesicular monoamine transporter type 2), and 11C-raclopride (RAC, dopamine D2/D3 receptors). One subject also underwent PET with 11C-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB, serotonin transporter). Results FDOPA-PET and DTBZ-PET in the affected individuals showed a reduction of striatal tracer uptake. Also, RAC-PET showed higher uptake in these area. DASB-PET showed significant uptake changes in left orbitofrontal cortex, bilateral anterior insula, left dorsolateral prefrontal cortex, left orbitofrontal cortex, left posterior cingulate cortex, left caudate, and left ventral striatum. Conclusions Our data showed evidence of both striatal dopaminergic and widespread cortical/subcortical serotonergic dysfunctions in individuals carrying a mutation in the DCTN1 gene. © 2014 International Parkinson and Movement Disorder Society
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Mayo Clinic Florida Collection Of Human Skin Fibroblast Cultures From Patients With Hereditary Neurodegenerative Disorders (P7.070)
Neurology, 2014Co-Authors: Zbigniew K. Wszolek, Pawel Tacik, Shinsuke Fujioka, Audrey Strongosky, Jing Zhao, Takahisa Kanekiyo, Guojun BuAbstract:OBJECTIVE: To collect and bank human skin fibroblasts from patients with genetically and clinically characterized neurodegenerative disorders at Mayo Clinic Florida. BACKGROUND: With recent technological advances in the field of regenerative medicine, studying the pathogenic mechanisms of neurodegenerative disorders is of paramount importance in order to both understand the disease and find cure. DESIGN/METHODS: The skin biopsy specimens were collected from 76 patients. RESULTS: The diagnoses included hereditary Parkinson’s disease (n=32; gene mutations: TDP43:p.N267S, PINK1:p.G411S, PINK1:p.I368N/p.I368N, PINK1:Q456X homozygote, LRRK2:R144C, LRRK2:G2019S, both heterozygote and homozygote, LRRK2:Y1699C, LRRK2:potential duplication, PARK2:R275W+intragene deletion, Parkin:Ex 4-7del/c.203_204del AG, Parkin:R275W/R275Q compound, SNCA: triplication, SNCA duplication, SNCA:A53T), pallido-ponto-nigral degeneration (n=7; gene: mutations: MAPT:N279K), ataxias (n=7, gene:mutations: FRD1: Allele1 1066 GAA repeats, Allele2: 366 GAA repeats, ATXN3: CAG repeats Allele1=71, Allele2=23, CACNA1A:R1346X, ATXN8OS, CACNA1A, exon 11 deletion), frontotemporal dementia (n=5, gene: mutations: MAPT:R406W, PGRN:c26C>A), amyotrophic lateral sclerosis (n=4, gene:mutations: TDP-43:G298S, SOD1:I113T, FUS:c.1561 C>G, C90RF72), dystonia (n=4, gene:mutations: THAP1:c.446T G p.K16E, SGCE:c.812G>A p.Cys271Tyr), frontotemporal dementia with parkinsonism linked to chromosome 17 (n= 4, gene:mutations: MAPT:V337M, MAPT:P301L), Perry Syndrome (n=4, gene:mutations: DCTN1:G71R, DCTN1:T72P), hereditary diffuse leukoencephalopathy with axonal spheroids (n=2, gene:mutations: CSF1R: p.M875T, CSF1R: p.C774_N814delinsQGLQSHVGPSLPSSSPQAQ), Alzheimer’s disease (n=2, gene:mutation: causative presenilin 1: G>A codon 97, nucleotide 537), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (n=1, NOTCH3), Huntington’s disease (n= 1; gene:mutation: IT15 CAG repeat Allele 1=22 Allele 2=40), McLeod Syndrome (n=1, XG gene), olivopontocerebellar atrophy (n=1, gene:mutation: C9ORF72, hexanucleotide expansion), and paroxysmal kinesigenic dyskinesia (n=1, gene:mutation: PRRT2 c.649dupC, p.R217Pfs*8). CONCLUSIONS: This large and growing collection of fibroblast cultures will be highly valuable for generation of induced pluripotent stem (iPS) cells for regenerative medicine projects by Mayo Clinic investigators and outside collaborators. Study Supported by: the NIH/NINDS RC2 NS070276 and P50 NS072187, Mayo Clinic Center for Regenerative Medicine, the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch, and the Max Kade Foundation. Disclosure: Dr. Wszolek has received personal compensation in an editorial capacity for Parkinsonism and Related Disorders, and for the European Journal of Neurology. Dr. Wszolek has received license fee payments from Mayo Clinic. Dr. Wright has received research support from the National Institutes of Health, Mayo Clinic Florida, and the Dystonia Medical Research Foundation. Dr. Tacik has nothing to disclose. Dr. Fujioka has nothing to disclose. Dr. Strongosky has received personal compensation for activities with Novartis, Eisai Inc., and the ANS. Dr. Zhao has nothing to disclose. Dr. Kanekiyo has nothing to disclose. Dr. Bu has nothing to disclose.
Yoshio Tsuboi - One of the best experts on this subject based on the ideXlab platform.
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Perry disease: recent advances and perspectives
Expert Opinion on Orphan Drugs, 2019Co-Authors: Takayasu Mishima, Shinsuke Fujioka, Yoshio TsuboiAbstract:Introduction: Perry disease, which is also widely known as Perry Syndrome, is a rare autosomal dominant neurodegenerative disease clinically characterized by parkinsonism, depression/apathy, weight...
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Modeling Parkinson's Disease and Atypical Parkinsonian Syndromes Using Induced Pluripotent Stem Cells.
International journal of molecular sciences, 2018Co-Authors: Takayasu Mishima, Junichi Yuasa-kawada, Shinsuke Fujioka, Jiro Fukae, Yoshio TsuboiAbstract: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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p150glued deficiency impairs effective fusion between autophagosomes and lysosomes due to their redistribution to the cell periphery.
Neuroscience letters, 2018Co-Authors: Kei-ichi Ishikawa, Yoshio Tsuboi, Shinji Saiki, Norihiko Furuya, Yoko Imamichi, Nobutaka HattoriAbstract:Dynein-dynactin has an indispensable role in autophagy and p150glued is the largest component of the dynactin complex. Here, we characterized the effects of knockdown (KD) of endogenous p150glued and of the pathogenic mutation of p150glued found in autosomal dominant p150glued-associated disorders [hereditary motor neuronopathy with vocal paresis (HMN7B) and Perry Syndrome] on autophagy. Overexpression of the p150glued pathogenic mutant or siRNA KD of p150glued promoted the localization of lysosomes at the cell periphery and increased the number of autophagosomes, suggesting partial blockage of autophagic flux. Surprisingly, although autophagosomes and lysosomes were redistributed predominantly to the cell periphery in p150glued-KD cells, the autolysosome formation ratio was preserved. However, under autophagy activation conditions induced by starvation, the ratio of autophagosome-lysosome fusion in p150glued-KD cells was decreased in the early phase. Our data demonstrate that functional loss of p150glued may cause autophagic insufficiency, which may be associated with the pathogenesis of p150glued-associated disorders.
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dctn1 f52l mutation case of Perry Syndrome with progressive supranuclear palsy like tauopathy
Parkinsonism & Related Disorders, 2018Co-Authors: Hiroyuki Honda, Chang Shen, Masahiro Shijo, Hideomi Hamasaki, Naokazu Sasagasako, Naoki Fujii, Yoshio Tsuboi, Satoshi O. Suzuki, Toru IwakiAbstract:Abstract Introduction Perry Syndrome is a rapidly progressive, autosomal dominant parkinsonism characterized by central hypoventilation, depression and severe weight loss. To date, eight DCTN1 mutations have been identified associated with Perry Syndrome. A novel F52L DCTN1 mutation case of Perry Syndrome is characterized by late-onset parkinsonism and frontotemporal atrophy. Methods A Japanese woman suffered from slowly progressing parkinsonism since age 48. At age 59, she developed central hypoventilation, and required breathing assistance. Gene analysis identified a p.F52L mutation in DCTN1 and she was diagnosed with Perry Syndrome. She died of aspiration pneumonia at age 74. Results Postmortem examination revealed severe neuronal loss in the substantia nigra and the putamen. Immunohistochemistry for DCTN1 revealed many abnormal aggregates, mainly in neurons in the brainstem and basal ganglia. Additionally, numerous abnormal phosphorylated tau deposits including neurofibrillary tangles, tuft-shaped astrocytes and coiled bodies were observed mainly in the basal ganglia, brainstem and cerebellum. These correspond with the neuropathologic criteria for progressive supranuclear palsy. Colocalization of DCTN1 and tau were occasionally seen. Colocalization of phosphorylated α-synuclein and DCTN1 were also observed in Lewy body-like structures in oculomotor nuclei. Phosphorylated TARDBP-positive neuronal cytoplasmic inclusions were few. Conclusion In conjunction with long disease duration and aging, our findings suggest that the F52L DCTN1 mutation may evoke severe tauopathy and moderate α-synucleinopathy.
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Modeling Parkinson’s Disease and Atypical Parkinsonian Syndromes Using Induced Pluripotent Stem Cells
MDPI AG, 2018Co-Authors: Takayasu Mishima, Junichi Yuasa-kawada, Shinsuke Fujioka, Jiro Fukae, Yoshio TsuboiAbstract: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
Dennis W Dickson - One of the best experts on this subject based on the ideXlab platform.
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Establishing diagnostic criteria for Perry Syndrome
Journal of Neurology Neurosurgery and Psychiatry, 2017Co-Authors: Takayasu Mishima, Owen A Ross, Ryoichi Kurisaki, Ichiro Yabe, Ryuji Neshige, Matthew J Farrer, Hiroyuki Tomiyama, Shinsuke Fujioka, Naoki Fujii, Dennis W DicksonAbstract:Objective To establish international diagnostic criteria for Perry Syndrome, a disorder characterised by clinical signs of parkinsonism, depression/apathy, weight loss, respiratory symptoms, mutations in the DCTN1 gene and TAR DNA-binding protein 43 (TDP-43) pathology. Methods Data from the published literature and newly identified patients were gathered and analysed during and after the International Symposium on Perry Syndrome in Tokyo to identify diagnostic criteria for Perry Syndrome. Results Eighty-seven patients with Perry Syndrome carrying DCTN1 mutations from 20 families were included in this study, and common signs of the disorder were identified, including parkinsonism (95.2% of patients), depression/apathy (71.4%), respiratory symptoms (66.7%) and weight loss (49.2%). Conclusions Based on our findings, we propose the following definitive diagnostic criteria for Perry Syndrome: the presence of four cardinal signs of Perry Syndrome, accompanied by a mutation in DCTN1; or a family history of the disease, parkinsonism and a mutation in DCTN1 ; or the presence of four cardinal signs and pathological findings that include nigral neuronal loss and TDP-43 pathology. As patients with Perry Syndrome present with uniform clinical, genetic and pathological features, we further propose the disorder be termed ‘Perry disease.’
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dctn1 related neurodegeneration Perry Syndrome and beyond
Parkinsonism & Related Disorders, 2017Co-Authors: Takuya Konno, Owen A Ross, Helio A G Teive, Jaroslaw Slawek, Dennis W Dickson, Zbigniew K. WszolekAbstract:Abstract 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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Perry Syndrome: A Distinctive Type of TDP-43 Proteinopathy.
Journal of Neuropathology and Experimental Neurology, 2017Co-Authors: Takayasu Mishima, Koji Kasanuki, Monica Castanedes-casey, Zbigniew K. Wszolek, Shin J Oh, Yoshio Tsuboi, Shunsuke Koga, Dennis W DicksonAbstract:Perry Syndrome is a rare atypical parkinsonism with depression, apathy, weight loss, and central hypoventilation caused by mutations in dynactin p150glued (DCTN1). A rare distal hereditary motor neuropathy, HMN7B, also has mutations in DCTN1. Perry Syndrome has TAR DNA-binding protein of 43 kDa (TDP-43) inclusions as a defining feature. Other TDP-43 proteinopathies include amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with and without motor neuron disease (FTLD-MND). TDP-43 forms aggregates in neuronal cytoplasmic inclusions (NCIs), neuronal intranuclear inclusions, dystrophic neurites (DNs), as well as axonal spheroids, oligodendroglial cytoplasmic inclusions, and perivascular astrocytic inclusions (PVIs). We performed semiquantitative assessment of these lesions and presence of dynactin subunit p50 lesions in 3 cases of Perry Syndrome and one of HMN7B. We compared them with 3 cases of FTLD-MND, 3 of ALS, and 3 of hippocampal sclerosis (HpScl). Perry Syndrome had NCIs, DNs, and frequent PVIs and spheroids. Perry Syndrome cases were similar, but different from ALS, FTLD-MND, and HpScl. TDP-43 pathology was not detected in HMN7B. Dynactin p50 inclusions were observed in both Perry Syndrome and HMN7B, but not in the other conditions. These results suggest that Perry Syndrome may be distinctive type of TDP-43 proteinopathy.
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Reduced orexin immunoreactivity in Perry Syndrome and multiple system atrophy.
Parkinsonism & related disorders, 2017Co-Authors: Takayasu Mishima, Koji Kasanuki, Monica Castanedes-casey, Zbigniew K. Wszolek, Yoshio Tsuboi, Shunsuke Koga, Dennis W DicksonAbstract:Abstract Introduction Orexin is a neuropeptide that plays a key role in maintaining a state of arousal, and possibly associates with sleep apnea Syndrome (SAS). Reduced orexin immunoreactivity has been reported in various neurologic conditions such as narcolepsy, Alzheimer’s disease, Lewy body disease and multiple system atrophy (MSA); however, there has been no report investigating orexin in Perry Syndrome, a rare hereditary neurodegenerative disease characterized by four clinical cardinal signs (parkinsonism, depression/apathy, weight loss, and central hypoventilation). Perry Syndrome patients frequently have sleep disturbances, including SAS and insomnia. Methods We evaluated orexin immunoreactivity in Perry Syndrome. Using imaging analysis, we quantitatively assessed orexin immunoreactivity in the nucleus basalis of Meynert in three Perry Syndrome cases, as well as five cases of frontotemporal lobar degeneration with motor neuron disease, five cases of MSA and five age-matched controls. For these cases, antemortem clinical information on sleep disturbances has been reviewed. Results In Perry Syndrome and MSA, there was reduction of orexin immunoreactivity compared with controls (Perry Syndrome: p = 0.020, MSA: p Conclusions This is the first report assessing orexin immunoreactivity in Perry Syndrome, and it showed significant reduction, similar to select neurodegenerative diseases, such as MSA. Further analysis with more cases will be needed to elucidate the specific mechanism of orexin loss in these disorders.
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Elucidating the genetics and pathology of Perry Syndrome.
Journal of the neurological sciences, 2009Co-Authors: Christian Wider, Justus C Dachsel, Matthew J Farrer, Dennis W Dickson, Yoshio Tsuboi, Zbigniew K. WszolekAbstract:Perry Syndrome is characterized clinically by autosomal dominantly inherited, rapidly progressive parkinsonism, depression, weight loss and hypoventilation. In the seven families reported previously and the two new families presented herein (the Hawaii family and the Fukuoka-4 Japanese family), the mean disease onset age is 48 years (range: 35-61) and the mean disease duration five years (range: 2-10). Histology and immunohistochemistry show severe neuronal loss in the substantia nigra and locus coeruleus, with TDP-43-positive pathology in neurons (intranuclear and cytoplasmic inclusions, dystrophic neurites, axonal spheroids) and glial cells (glial cytoplasmic inclusions). Compared with other TDP-43-proteinopathies (amyotrophic lateral sclerosis and ubiquitin-positive frontotemporal lobar degeneration), the distribution is unique in Perry Syndrome with pallidonigral distribution and sparing of the cortex, hippocampus and motor neurons. The genetic cause of Perry Syndrome was recently identified with five mutations in the dynactin gene (DCTN1) segregating with disease in eight families. DCTN1 encodes p150(glued), the major subunit of the dynactin protein complex, which plays a crucial role in retrograde axonal and cytoplasmic transport of various cargoes. Evidence suggests the Perry mutations alter the binding of p150(glued) to microtubules. Further studies will examine reasons for the vulnerability of selected neuronal populations in Perry Syndrome, and the link between the genetic defect and TDP-43 pathology.
Takayasu Mishima - One of the best experts on this subject based on the ideXlab platform.
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Meta-iodobenzylguanidine myocardial scintigraphy in Perry disease
Parkinsonism & related disorders, 2021Co-Authors: Takayasu Mishima, Ichiro Yabe, Shinsuke Fujioka, Kenya Nishioka, Kazunori Sato, Hideki Houzen, Kazutaka Shiomi, Makoto Eriguchi, Hideo HaraAbstract:Abstract Introduction Perry disease (Perry Syndrome), a hereditary TAR DNA-binding protein 43 (TDP-43) proteinopathy, is caused by dynactin subunit 1 (DCNT1) mutations and is characterized by rapidly progressive parkinsonism accompanied by depression, apathy, unexpected weight loss, and respiratory symptoms including central hypoventilation and central sleep apnea. Meta-iodobenzylguanidine (MIBG) myocardial scintigraphy is considered a diagnostic biomarker for Lewy body disease (LBD), as denervation of cardiac sympathetic nerves is a pathological feature in LBD. However, our previous studies have reported a decreased cardiac uptake of MIBG in patients with Perry disease. In this study, we aimed to correlate the MIBG myocardial scintigraphy findings with clinical features in Perry disease. Methods We evaluated data obtained from a multicenter survey of patients of Japanese origin with suspected Perry disease, who visited neurology departments in Japan from January 2010 to December 2018. We screened each patient's DNA for the DCTN1 mutation using Sanger sequencing and obtained the clinical details of all patients including findings from their MIBG myocardial scintigraphy. Results We identified two novel mutations, p.G71V and p.K68E, in DCTN1 in patients from two different families. The majority of patients (7/8, 87.5%) showed a decrease in cardiac uptake (heart to mediastinum ratio) in MIBG myocardial scintigraphy. These patients commonly presented with symptoms related to autonomic dysfunction: constipation, fecal incontinence, urinary disturbance, and orthostatic hypotension. Conclusions MIBG myocardial scintigraphy may be a useful biomarker of autonomic dysfunction in Perry disease.
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Perry disease: recent advances and perspectives
Expert Opinion on Orphan Drugs, 2019Co-Authors: Takayasu Mishima, Shinsuke Fujioka, Yoshio TsuboiAbstract:Introduction: Perry disease, which is also widely known as Perry Syndrome, is a rare autosomal dominant neurodegenerative disease clinically characterized by parkinsonism, depression/apathy, weight...
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Modeling Parkinson's Disease and Atypical Parkinsonian Syndromes Using Induced Pluripotent Stem Cells.
International journal of molecular sciences, 2018Co-Authors: Takayasu Mishima, Junichi Yuasa-kawada, Shinsuke Fujioka, Jiro Fukae, Yoshio TsuboiAbstract: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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Modeling Parkinson’s Disease and Atypical Parkinsonian Syndromes Using Induced Pluripotent Stem Cells
MDPI AG, 2018Co-Authors: Takayasu Mishima, Junichi Yuasa-kawada, Shinsuke Fujioka, Jiro Fukae, Yoshio TsuboiAbstract: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
Neuroscience Letters, 2017Co-Authors: Takayasu Mishima, Manami Deshimaru, Kaori Kubota, Mariko Kinoshita-kawada, Junichi Yuasa-kawada, Shozo Jinno, Yoshinari Uehara, Takuya Watanabe, Kotaro Takasaki, Katsunori IwasakiAbstract:Abstract Perry Syndrome is a rare neurodegenerative disease characterized by parkinsonism, depression/apathy, weight loss, and central hypoventilation. Our previously-conducted genome-wide association scan and subsequent studies identified nine mutations in DCTN1, the largest protein subunit of the dynactin complex, in patients with Perry Syndrome. These included G71A in the microtubule-binding cytoskeleton-associated protein Gly-rich domain of p150Glued. The dynactin complex is essential for function of the microtubule-based cytoplasmic retrograde motor dynein. To test the hypothesis that the G71A mutation in the DCTN1 gene is sufficient to cause Perry Syndrome, we generated DCTN1G71A transgenic mice. These mice initially developed normally, but young animals showed decreased exploratory activity and aged animals showed impaired motor coordination. These behavioral defects parallel apathy-like symptoms and parkinsonism encountered in Perry Syndrome. TDP-43 aggregates were not detected in the substantia nigra and cerebral cortex of the transgenic mice, although pathological aggregates of TDP-43 have been considered a major neuropathological feature of Perry Syndrome. Our study reveals that a single mutation in the DCTN1 gene recapitulates symptoms of Perry Syndrome patients, and provides evidence that DCTN1G71A transgenic mice represent a novel rodent model of Perry Syndrome.
Shinsuke Fujioka - One of the best experts on this subject based on the ideXlab platform.
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Meta-iodobenzylguanidine myocardial scintigraphy in Perry disease
Parkinsonism & related disorders, 2021Co-Authors: Takayasu Mishima, Ichiro Yabe, Shinsuke Fujioka, Kenya Nishioka, Kazunori Sato, Hideki Houzen, Kazutaka Shiomi, Makoto Eriguchi, Hideo HaraAbstract:Abstract Introduction Perry disease (Perry Syndrome), a hereditary TAR DNA-binding protein 43 (TDP-43) proteinopathy, is caused by dynactin subunit 1 (DCNT1) mutations and is characterized by rapidly progressive parkinsonism accompanied by depression, apathy, unexpected weight loss, and respiratory symptoms including central hypoventilation and central sleep apnea. Meta-iodobenzylguanidine (MIBG) myocardial scintigraphy is considered a diagnostic biomarker for Lewy body disease (LBD), as denervation of cardiac sympathetic nerves is a pathological feature in LBD. However, our previous studies have reported a decreased cardiac uptake of MIBG in patients with Perry disease. In this study, we aimed to correlate the MIBG myocardial scintigraphy findings with clinical features in Perry disease. Methods We evaluated data obtained from a multicenter survey of patients of Japanese origin with suspected Perry disease, who visited neurology departments in Japan from January 2010 to December 2018. We screened each patient's DNA for the DCTN1 mutation using Sanger sequencing and obtained the clinical details of all patients including findings from their MIBG myocardial scintigraphy. Results We identified two novel mutations, p.G71V and p.K68E, in DCTN1 in patients from two different families. The majority of patients (7/8, 87.5%) showed a decrease in cardiac uptake (heart to mediastinum ratio) in MIBG myocardial scintigraphy. These patients commonly presented with symptoms related to autonomic dysfunction: constipation, fecal incontinence, urinary disturbance, and orthostatic hypotension. Conclusions MIBG myocardial scintigraphy may be a useful biomarker of autonomic dysfunction in Perry disease.
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Perry disease: recent advances and perspectives
Expert Opinion on Orphan Drugs, 2019Co-Authors: Takayasu Mishima, Shinsuke Fujioka, Yoshio TsuboiAbstract:Introduction: Perry disease, which is also widely known as Perry Syndrome, is a rare autosomal dominant neurodegenerative disease clinically characterized by parkinsonism, depression/apathy, weight...
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Modeling Parkinson's Disease and Atypical Parkinsonian Syndromes Using Induced Pluripotent Stem Cells.
International journal of molecular sciences, 2018Co-Authors: Takayasu Mishima, Junichi Yuasa-kawada, Shinsuke Fujioka, Jiro Fukae, Yoshio TsuboiAbstract: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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Modeling Parkinson’s Disease and Atypical Parkinsonian Syndromes Using Induced Pluripotent Stem Cells
MDPI AG, 2018Co-Authors: Takayasu Mishima, Junichi Yuasa-kawada, Shinsuke Fujioka, Jiro Fukae, Yoshio TsuboiAbstract: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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Establishing diagnostic criteria for Perry Syndrome
Journal of Neurology Neurosurgery and Psychiatry, 2017Co-Authors: Takayasu Mishima, Owen A Ross, Ryoichi Kurisaki, Ichiro Yabe, Ryuji Neshige, Matthew J Farrer, Hiroyuki Tomiyama, Shinsuke Fujioka, Naoki Fujii, Dennis W DicksonAbstract:Objective To establish international diagnostic criteria for Perry Syndrome, a disorder characterised by clinical signs of parkinsonism, depression/apathy, weight loss, respiratory symptoms, mutations in the DCTN1 gene and TAR DNA-binding protein 43 (TDP-43) pathology. Methods Data from the published literature and newly identified patients were gathered and analysed during and after the International Symposium on Perry Syndrome in Tokyo to identify diagnostic criteria for Perry Syndrome. Results Eighty-seven patients with Perry Syndrome carrying DCTN1 mutations from 20 families were included in this study, and common signs of the disorder were identified, including parkinsonism (95.2% of patients), depression/apathy (71.4%), respiratory symptoms (66.7%) and weight loss (49.2%). Conclusions Based on our findings, we propose the following definitive diagnostic criteria for Perry Syndrome: the presence of four cardinal signs of Perry Syndrome, accompanied by a mutation in DCTN1; or a family history of the disease, parkinsonism and a mutation in DCTN1 ; or the presence of four cardinal signs and pathological findings that include nigral neuronal loss and TDP-43 pathology. As patients with Perry Syndrome present with uniform clinical, genetic and pathological features, we further propose the disorder be termed ‘Perry disease.’