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Article ; Online: Proteomic analysis of heat-stable proteins revealed an increased proportion of proteins with compositionally biased regions.

Park, Hongsun / Yamanaka, Tomoyuki / Nukina, Nobuyuki

2022 Volume 12, Issue 1, Page(s) 4347

Abstract: Intrinsically disordered proteins (IDPs) have been in the spotlight for their unique properties, such as their lack of secondary structures and low sequence complexity. Alpha-synuclein and tau are representative disease-related IDPs with low complexity ... ...

Abstract	Intrinsically disordered proteins (IDPs) have been in the spotlight for their unique properties, such as their lack of secondary structures and low sequence complexity. Alpha-synuclein and tau are representative disease-related IDPs with low complexity regions in their sequences, accumulating in the brains of patients with Parkinson disease and Alzheimer disease, respectively. Their heat resistance in particular was what attracted our attention. We assumed that there exist many other unidentified proteins that are resistant to heat-treatment, referred to as heat-stable proteins, which would also have low sequence complexity. In this study, we performed proteomic analysis of heat-stable proteins of mouse brains and found that proteins with compositionally biased regions are abundant in the heat-stable proteins. The proteins related to neurodegeneration are known to undergo different types of post-translational modifications (PTMs) such as phosphorylation and ubiquitination. We then investigated the heat-stability and aggregation properties of phosphorylated synuclein and tau with different phosphorylation sites. We suggest that PTMs can be important factors that determine the heat-stability and aggregation properties of a protein. IDPs identified in the heat-stable proteins of mouse brains would be candidates for the pathogenic proteins for neurodegeneration.
MeSH term(s)	Animals ; Hot Temperature ; Humans ; Intrinsically Disordered Proteins/chemistry ; Mice ; Protein Processing, Post-Translational ; Protein Structure, Secondary ; Proteomics
Chemical Substances	Intrinsically Disordered Proteins
Language	English
Publishing date	2022-03-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-08044-z
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Article ; Online: Amyloids facilitate DNA transfection in vivo.

Imamura, Yukio / Hiyama, Akiko / Miyazaki, Haruko / Yamanaka, Tomoyuki / Nukina, Nobuyuki

Neuroscience research

2022 Volume 180, Page(s) 99–107

Abstract: Amyloid fibril deposits are a main source of pathology in neurodegenerative diseases. Normal proteins such as tau, alpha-synuclein, TDP-43 and others could form specific conformational fibrils called amyloid, which deposited in the brains of ... ...

Abstract	Amyloid fibril deposits are a main source of pathology in neurodegenerative diseases. Normal proteins such as tau, alpha-synuclein, TDP-43 and others could form specific conformational fibrils called amyloid, which deposited in the brains of neurodegenerative diseases. Although the pathological roles of amyloids in cell death have been discussed a lot, their other functions have not been investigated well. Here, we studied the effect of amyloids on DNA transfection in vivo. We injected quantum dot labeled or non-labeled amyloid-preformed fibrils (PFFs) and a green fluorescent protein (EGFP) expression vector into organs including brain, testis, liver and calf muscle. GFP expression patterns were examined by immunohistochemistry and western blotting. At 24 h after injection, EGFP was predominantly expressed in the neurons in the cortex and the striatum, Leydig cells in testis, hepatocytes in the liver and muscle cells. EGFP expression was inhibited by an endocytosis inhibitor, sertraline in the brain and testis. The amyloid-PFFs potentiated Ca
MeSH term(s)	Amyloid ; DNA/metabolism ; Green Fluorescent Proteins/genetics ; Green Fluorescent Proteins/metabolism ; Humans ; Male ; Neurons/metabolism ; Transfection ; alpha-Synuclein/metabolism
Chemical Substances	Amyloid ; alpha-Synuclein ; Green Fluorescent Proteins (147336-22-9) ; DNA (9007-49-2)
Language	English
Publishing date	2022-03-10
Publishing country	Ireland
Document type	Journal Article
ZDB-ID	605842-5
ISSN	1872-8111 ; 0168-0102 ; 0921-8696
ISSN (online)	1872-8111
ISSN	0168-0102 ; 0921-8696
DOI	10.1016/j.neures.2022.03.003
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Article ; Online: The diffuse distribution of Nav1.2 on mid-axonal regions is a marker for unmyelinated fibers in the central nervous system.

Yamano, Risa / Miyazaki, Haruko / Nukina, Nobuyuki

Neuroscience research

2021 Volume 177, Page(s) 145–150

Abstract: Unmyelinated fibers in the central nervous system are known to exist in hippocampal mossy fibers, cerebellar parallel fibers and striatal projection fibers. Previously, we and others reported diffuse distribution of Nav1.2, a voltage-gated sodium channel ...

Abstract	Unmyelinated fibers in the central nervous system are known to exist in hippocampal mossy fibers, cerebellar parallel fibers and striatal projection fibers. Previously, we and others reported diffuse distribution of Nav1.2, a voltage-gated sodium channel α-subunit encoded by the SCN2A gene, on unmyelinated striatal projection fibers. Mutations in the SCN2A gene are associated with epilepsies and autism. In this study, we investigated the distribution of Nav1.2 on the unmyelinated fibers in the corpus callosum and stria terminalis by immunohistochemistry and immunoelectron microscopy analysis, suggesting that diffuse localization of Nav1.2 on mid-axonal regions can be a useful marker for unmyelinated fibers.
MeSH term(s)	Axons/physiology ; Central Nervous System ; Immunohistochemistry ; NAV1.2 Voltage-Gated Sodium Channel ; Voltage-Gated Sodium Channels
Chemical Substances	NAV1.2 Voltage-Gated Sodium Channel ; Voltage-Gated Sodium Channels
Language	English
Publishing date	2021-11-19
Publishing country	Ireland
Document type	Journal Article
ZDB-ID	605842-5
ISSN	1872-8111 ; 0168-0102 ; 0921-8696
ISSN (online)	1872-8111
ISSN	0168-0102 ; 0921-8696
DOI	10.1016/j.neures.2021.11.005
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Article ; Online: Mutant VAPB: Culprit or Innocent Bystander of Amyotrophic Lateral Sclerosis?

Borgese, Nica / Navone, Francesca / Nukina, Nobuyuki / Yamanaka, Tomoyuki

Contact (Thousand Oaks (Ventura County, Calif.))

2021 Volume 4, Page(s) 25152564211022515

Abstract: Nearly twenty years ago a mutation in the VAPB gene, resulting in a proline to serine substitution (p.P56S), was identified as the cause of a rare, slowly progressing, familial form of the motor neuron degenerative disease Amyotrophic Lateral Sclerosis ( ... ...

Abstract	Nearly twenty years ago a mutation in the VAPB gene, resulting in a proline to serine substitution (p.P56S), was identified as the cause of a rare, slowly progressing, familial form of the motor neuron degenerative disease Amyotrophic Lateral Sclerosis (ALS). Since then, progress in unravelling the mechanistic basis of this mutation has proceeded in parallel with research on the VAP proteins and on their role in establishing membrane contact sites between the ER and other organelles. Analysis of the literature on cellular and animal models reviewed here supports the conclusion that P56S-VAPB, which is aggregation-prone, non-functional and unstable, is expressed at levels that are insufficient to support toxic gain-of-function or dominant negative effects within motor neurons. Instead, insufficient levels of the product of the single wild-type allele appear to be required for pathological effects, and may be the main driver of the disease. In light of the multiple interactions of the VAP proteins, we address the consequences of specific VAPB depletion and highlight various affected processes that could contribute to motor neuron degeneration. In the future, distinction of specific roles of each of the two VAP paralogues should help to further elucidate the basis of p.P56S familial ALS, as well as of other more common forms of the disease.
Language	English
Publishing date	2021-06-15
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2964312-0
ISSN	2515-2564 ; 2515-2564
ISSN (online)	2515-2564
ISSN	2515-2564
DOI	10.1177/25152564211022515
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Article ; Online: The transcription factor NF-YA is crucial for neural progenitor maintenance during brain development.

Yamanaka, Tomoyuki / Kurosawa, Masaru / Yoshida, Aya / Shimogori, Tomomi / Hiyama, Akiko / Maity, Sankar N / Hattori, Nobutaka / Matsui, Hideaki / Nukina, Nobuyuki

The Journal of biological chemistry

2024 Volume 300, Issue 2, Page(s) 105629

Abstract: In contrast to stage-specific transcription factors, the role of ubiquitous transcription factors in neuronal development remains a matter of scrutiny. Here, we demonstrated that a ubiquitous factor NF-Y is essential for neural progenitor maintenance ... ...

Abstract	In contrast to stage-specific transcription factors, the role of ubiquitous transcription factors in neuronal development remains a matter of scrutiny. Here, we demonstrated that a ubiquitous factor NF-Y is essential for neural progenitor maintenance during brain morphogenesis. Deletion of the NF-YA subunit in neural progenitors by using nestin-cre transgene in mice resulted in significant abnormalities in brain morphology, including a thinner cerebral cortex and loss of striatum during embryogenesis. Detailed analyses revealed a progressive decline in multiple neural progenitors in the cerebral cortex and ganglionic eminences, accompanied by induced apoptotic cell death and reduced cell proliferation. In neural progenitors, the NF-YA short isoform lacking exon 3 is dominant and co-expressed with cell cycle genes. ChIP-seq analysis from the cortex during early corticogenesis revealed preferential binding of NF-Y to the cell cycle genes, some of which were confirmed to be downregulated following NF-YA deletion. Notably, the NF-YA short isoform disappears and is replaced by its long isoform during neuronal differentiation. Forced expression of the NF-YA long isoform in neural progenitors resulted in a significant decline in neuronal count, possibly due to the suppression of cell proliferation. Collectively, we elucidated a critical role of the NF-YA short isoform in maintaining neural progenitors, possibly by regulating cell proliferation and apoptosis. Moreover, we identified an isoform switch in NF-YA within the neuronal lineage in vivo, which may explain the stage-specific role of NF-Y during neuronal development.
MeSH term(s)	Animals ; Mice ; CCAAT-Binding Factor/genetics ; CCAAT-Binding Factor/metabolism ; Cerebral Cortex/cytology ; Cerebral Cortex/growth & development ; Cerebral Cortex/metabolism ; Gene Expression Regulation ; Neurogenesis ; Protein Isoforms/genetics ; Protein Isoforms/metabolism ; Transcription Factors/metabolism
Chemical Substances	CCAAT-Binding Factor ; Protein Isoforms ; Transcription Factors ; Nfya protein, mouse
Language	English
Publishing date	2024-01-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2024.105629
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Article ; Online: [Neurodegeration based on polyglutamine aggregation].

Nukina, Nobuyuki

Rinsho shinkeigaku = Clinical neurology

2012 Volume 51, Issue 11, Page(s) 976–978

Abstract: One of the major hypotheses about polyQ toxicity is the sequestration of functionally important proteins into the aggregates. We established and carried out a direct, systematic proteomic analysis of aggregate-interacting proteins (AIPs). This analysis, ... ...

Abstract	One of the major hypotheses about polyQ toxicity is the sequestration of functionally important proteins into the aggregates. We established and carried out a direct, systematic proteomic analysis of aggregate-interacting proteins (AIPs). This analysis, as well as other studies in our lab, has revealed the following AIPs in addition to our previously reported chaperones: ubiquitin binding proteins such as ubiquilins and Tollip and p62, TLS and transcription factor NF-Y. Although transcriptional dysregulation has been reported in polyQ disease, the precise mechanism has not been clarified. We identified NF-Y as an AIP and found the reduction of NF-Y binding to the promoter region of HSP70, one of the NF-Y targets. Because suppressive roles of HSP70 on the HD pathological process have been shown in several HD models, NF-Y could be an important target of expanded polyQ. We further screened transcription factors, which reduced in HD model mouse, using Protein DNA array and found the decrease of POU domain factor. Based on this result, we confirmed Brn2 is decreased in HD model mouse, which showed the dysfunction of hypothalamus. We proposed the mechanism of hypothalamic dysregulation, suggesting the region specific abnormality could be induced by the imbalance of cellular compensatory mechanism.
MeSH term(s)	Animals ; Mice ; Neurodegenerative Diseases/metabolism ; Peptides/analysis ; RNA-Binding Proteins/physiology
Chemical Substances	Peptides ; RNA-Binding Proteins ; polyglutamine (26700-71-0)
Language	Japanese
Publishing date	2012-01-03
Publishing country	Japan
Document type	English Abstract ; Journal Article
ZDB-ID	604200-4
ISSN	1882-0654 ; 0009-918X
ISSN (online)	1882-0654
ISSN	0009-918X
DOI	10.5692/clinicalneurol.51.976
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Zs.MO 223: Show issues

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Article: ER Dynamics and Derangement in Neurological Diseases.

Yamanaka, Tomoyuki / Nukina, Nobuyuki

Frontiers in neuroscience

2018 Volume 12, Page(s) 91

Abstract: The endoplasmic reticulum (ER) is a morphologically dynamic organelle containing different membrane subdomains with distinct cellular functions. Numerous observations have revealed that ER stress response induced by disturbed ER homeostasis is linked to ... ...

Abstract	The endoplasmic reticulum (ER) is a morphologically dynamic organelle containing different membrane subdomains with distinct cellular functions. Numerous observations have revealed that ER stress response induced by disturbed ER homeostasis is linked to various neurological/neurodegenerative disorders. In contrast, recent findings unveil that ER structural derangements are linked to the progression of several neurological diseases. The derangements involve two distinct, and likely opposing pathways. One is dysfunction of ER dynamics machinery, leading to disruption of ER network organization. Another one is facilitation of pre-existing machinery, leading to generation of markedly-ordered
Language	English
Publishing date	2018-02-20
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-4548
ISSN (online)	1662-453X
ISSN	1662-4548
DOI	10.3389/fnins.2018.00091
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Article ; Online: Proteomics-Based Approach Identifies Altered ER Domain Properties by ALS-Linked VAPB Mutation.

Yamanaka, Tomoyuki / Nishiyama, Risa / Shimogori, Tomomi / Nukina, Nobuyuki

Scientific reports

2020 Volume 10, Issue 1, Page(s) 7610

Abstract: An ER transmembrane protein, vesicle-associated membrane protein-associated protein B (VAPB), binds to several organelle-resident membrane proteins to mediate ER-organelle tethering. Mutation in amyotrophic lateral sclerosis (ALS) induces protein ... ...

Abstract	An ER transmembrane protein, vesicle-associated membrane protein-associated protein B (VAPB), binds to several organelle-resident membrane proteins to mediate ER-organelle tethering. Mutation in amyotrophic lateral sclerosis (ALS) induces protein misfolding and aggregation, leading to ER disorganization. Gain or loss of function is suggested for VAPB mutation, however comprehensive study focusing on VAPB-ER domain has yet been performed. We here conducted proteomic characterization of the ER containing VAPB and its ALS-linked P56S mutant. For this purpose, we first optimized the proteomics of different ER domains immuno-isolated from cultured cells, and identified ER sheet- and tubule-specific proteomes. By using these as references, we found that VAPB-ER proteome had intermediate ER domain properties but its tubular property was specifically decreased by its mutation. Biochemical, immunofluorescence and proximity ligation assays suggested this was mediated by delocalization of VAPB from ER tubules. The VAPB-ER proteomics further suggested reduced incorporation of multiple proteins located in different organelles, which was confirmed by proximity ligation assay. Taken together, our proteomics-based approach indicates altered ER domain properties and impaired ER-organelle tethering by VAPB mutation.
MeSH term(s)	Amyotrophic Lateral Sclerosis/genetics ; Animals ; Cell Line ; Endoplasmic Reticulum/metabolism ; Mice ; Mutation ; Protein Domains ; Protein Interaction Mapping ; Proteomics ; Vesicular Transport Proteins/chemistry ; Vesicular Transport Proteins/genetics ; Vesicular Transport Proteins/metabolism
Chemical Substances	VAPB protein, mouse ; Vesicular Transport Proteins
Language	English
Publishing date	2020-05-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-64517-z
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Article ; Online: [FUS/TLS as a polyglutamine aggregate interacting protein].

Nukina, Nobuyuki

Rinsho shinkeigaku = Clinical neurology

2011 Volume 50, Issue 11, Page(s) 945–947

Abstract: Formation of intracellular aggregates is the hallmark of polyglutamine (polyQ) diseases. We analyzed the components of purified nuclear polyQ aggregates by mass spectrometry. As a result, we found that the RNA-binding protein translocated in liposarcoma ( ...

Abstract	Formation of intracellular aggregates is the hallmark of polyglutamine (polyQ) diseases. We analyzed the components of purified nuclear polyQ aggregates by mass spectrometry. As a result, we found that the RNA-binding protein translocated in liposarcoma (TLS) was one of the major components of nuclear polyQ aggregate-interacting proteins in a Huntington disease cell model and was also associated with neuronal intranuclear inclusions of polyQ diseases. In vitro study revealed that TLS could directly bind to truncated N-terminal huntingtin (tNhtt) aggregates but could not bind to monomer, indicating that the tNhtt protein acquired the ability to sequester TLS after forming aggregates. Immunohistochemistry showed that TLS was associated with neuronal intranuclear inclusions of Huntington disease and other poly Q disease brains. After this report, FUS/TLS was reported as a responsible gene for ALS6. Because TLS has a variety of functional roles, the sequestration of TLS to polyQ aggregates may play a role in diverse pathological changes in the brains of patients with polyQ diseases and ALS6.
MeSH term(s)	Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/pathology ; Animals ; Brain/metabolism ; Brain/pathology ; Humans ; Huntington Disease/genetics ; Huntington Disease/pathology ; Mice ; Mutation ; Peptides/metabolism ; Protein Binding ; Protein Folding ; RNA-Binding Protein FUS/genetics ; RNA-Binding Protein FUS/physiology
Chemical Substances	Peptides ; RNA-Binding Protein FUS ; polyglutamine (26700-71-0)
Language	Japanese
Publishing date	2011-09-16
Publishing country	Japan
Document type	English Abstract ; Journal Article ; Review
ZDB-ID	604200-4
ISSN	1882-0654 ; 0009-918X
ISSN (online)	1882-0654
ISSN	0009-918X
DOI	10.5692/clinicalneurol.50.945
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Article ; Online: Generation and characterization of cerebellar granule neurons specific knockout mice of Golli-MBP.

Miyazaki, Haruko / Nishioka, Saki / Yamanaka, Tomoyuki / Abe, Manabu / Imamura, Yukio / Miyasaka, Tomohiro / Kakuda, Nobuto / Oohashi, Toshitaka / Shimogori, Tomomi / Yamakawa, Kazuhiro / Ikawa, Masahito / Nukina, Nobuyuki

Transgenic research

2024

Abstract: Golli-myelin basic proteins, encoded by the myelin basic protein gene, are widely expressed in neurons and oligodendrocytes in the central nervous system. Further, prior research has shown that Golli-myelin basic protein is necessary for myelination and ... ...

Abstract	Golli-myelin basic proteins, encoded by the myelin basic protein gene, are widely expressed in neurons and oligodendrocytes in the central nervous system. Further, prior research has shown that Golli-myelin basic protein is necessary for myelination and neuronal maturation during central nervous system development. In this study, we established Golli-myelin basic protein-floxed mice to elucidate the cell-type-specific effects of Golli-myelin basic protein knockout through the generation of conditional knockout mice (Golli-myelin basic proteins
Language	English
Publishing date	2024-04-29
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	31620-9
ISSN	1573-9368 ; 0962-8819
ISSN (online)	1573-9368
ISSN	0962-8819
DOI	10.1007/s11248-024-00382-0
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