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Article ; Online: Aspects of degradation and translation of the expanded C9orf72 hexanucleotide repeat RNA.

Mori, Kohji / Gotoh, Shiho / Ikeda, Manabu

2023 Volume 166, Issue 2, Page(s) 156–171

Abstract: An hexanucleotide repeat expansion mutation in the non-coding region of C9orf72 gene causes frontotemporal dementia and amyotrophic lateral sclerosis. This mutation is estimated to be the most frequent genetic cause of these currently incurable diseases. ...

Abstract	An hexanucleotide repeat expansion mutation in the non-coding region of C9orf72 gene causes frontotemporal dementia and amyotrophic lateral sclerosis. This mutation is estimated to be the most frequent genetic cause of these currently incurable diseases. Since the mutation causes autosomal dominantly inherited diseases, disease cascade essentially starts from the expanded DNA repeats. However, molecular disease mechanism is inevitably complex because possible toxic entity for the disease is not just functional loss of translated C9ORF72 protein, if any, but potentially includes bidirectionally transcribed expanded repeat containing RNA and their unconventional repeat-associated non-AUG translation products in all possible reading frames. Although the field learned so much about the disease since the identification of the mutation in 2011, how the expanded repeat causes a particular type of fronto-temporal lobe dominant neurodegeneration and/or motor neuron degeneration is not yet clear. In this review, we summarize and discuss the current understandings of molecular mechanism of this repeat expansion mutation with focuses on the degradation and translation of the repeat containing RNA transcripts.
MeSH term(s)	Humans ; C9orf72 Protein/genetics ; Proteins/genetics ; Proteins/metabolism ; RNA/genetics ; RNA/metabolism ; Frontotemporal Dementia/genetics ; Amyotrophic Lateral Sclerosis/genetics ; DNA Repeat Expansion/genetics
Chemical Substances	C9orf72 Protein ; Proteins ; RNA (63231-63-0) ; C9orf72 protein, human
Language	English
Publishing date	2023-06-05
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	80158-6
ISSN	1471-4159 ; 0022-3042 ; 1474-1644
ISSN (online)	1471-4159
ISSN	0022-3042 ; 1474-1644
DOI	10.1111/jnc.15847
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Article ; Online: PABPC1 mediates degradation of

Uozumi, Ryota / Mori, Kohji / Gotoh, Shiho / Miyamoto, Tesshin / Kondo, Shizuko / Yamashita, Tomoko / Kawabe, Yuya / Tagami, Shinji / Akamine, Shoshin / Ikeda, Manabu

iScience

2024 Volume 27, Issue 3, Page(s) 109303

Abstract: GGGGCC hexanucleotide repeat expansion ... ...

Abstract	GGGGCC hexanucleotide repeat expansion in
Language	English
Publishing date	2024-02-22
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2024.109303
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Article ; Online: eIF5 stimulates the CUG initiation of RAN translation of poly-GA dipeptide repeat protein (DPR) in C9orf72 FTLD/ALS.

Gotoh, Shiho / Mori, Kohji / Fujino, Yuzo / Kawabe, Yuya / Yamashita, Tomoko / Omi, Tsubasa / Nagata, Kenichi / Tagami, Shinji / Nagai, Yoshitaka / Ikeda, Manabu

The Journal of biological chemistry

2024 Volume 300, Issue 3, Page(s) 105703

Abstract: Tandem GGGGCC repeat expansion in C9orf72 is a genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Transcribed repeats are translated into dipeptide repeat proteins via repeat-associated non-AUG (RAN) ... ...

Abstract	Tandem GGGGCC repeat expansion in C9orf72 is a genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Transcribed repeats are translated into dipeptide repeat proteins via repeat-associated non-AUG (RAN) translation. However, the regulatory mechanism of RAN translation remains unclear. Here, we reveal a GTPase-activating protein, eukaryotic initiation factor 5 (eIF5), which allosterically facilitates the conversion of eIF2-bound GTP into GDP upon start codon recognition, as a novel modifier of C9orf72 RAN translation. Compared to global translation, eIF5, but not its inactive mutants, preferentially stimulates poly-GA RAN translation. RAN translation is increased during integrated stress response, but the stimulatory effect of eIF5 on poly-GA RAN translation was additive to the increase of RAN translation during integrated stress response, with no further increase in phosphorylated eIF2α. Moreover, an alteration of the CUG near cognate codon to CCG or AUG in the poly-GA reading frame abolished the stimulatory effects, indicating that eIF5 primarily acts through the CUG-dependent initiation. Lastly, in a Drosophila model of C9orf72 FTLD/ALS that expresses GGGGCC repeats in the eye, knockdown of endogenous eIF5 by two independent RNAi strains significantly reduced poly-GA expressions, confirming in vivo effect of eIF5 on poly-GA RAN translation. Together, eIF5 stimulates the CUG initiation of poly-GA RAN translation in cellular and Drosophila disease models of C9orf72 FTLD/ALS.
MeSH term(s)	Animals ; Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/physiopathology ; C9orf72 Protein/genetics ; Dipeptides/genetics ; DNA Repeat Expansion/genetics ; Drosophila/genetics ; Drosophila/metabolism ; Eukaryotic Initiation Factor-5/genetics ; Eukaryotic Initiation Factor-5/metabolism ; Frontotemporal Lobar Degeneration/genetics ; Frontotemporal Lobar Degeneration/physiopathology ; HeLa Cells ; Humans ; Disease Models, Animal
Chemical Substances	C9orf72 Protein ; Dipeptides ; Eukaryotic Initiation Factor-5
Language	English
Publishing date	2024-01-30
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.2024.105703
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Article ; Online: The RNA exosome complex degrades expanded hexanucleotide repeat RNA in C9orf72 FTLD/ALS.

Kawabe, Yuya / Mori, Kohji / Yamashita, Tomoko / Gotoh, Shiho / Ikeda, Manabu

The EMBO journal

2020 Volume 39, Issue 19, Page(s) e102700

Abstract: Nucleotide repeat expansions in the C9orf72 gene cause frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Transcribed repeat RNA accumulates within RNA foci and is also translated into toxic dipeptide repeat proteins (DPR). ...

Abstract	Nucleotide repeat expansions in the C9orf72 gene cause frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Transcribed repeat RNA accumulates within RNA foci and is also translated into toxic dipeptide repeat proteins (DPR). The mechanism of repeat RNA accumulation, however, remains unclear. The RNA exosome complex is a multimeric ribonuclease involved in degradation of defective RNA. Here, we uncover the RNA exosome as a major degradation complex for pathogenic C9orf72-derived repeat RNA. Knockdown of EXOSC10, the catalytic subunit of the complex, enhanced repeat RNA and DPR protein expression levels. RNA degradation assays confirmed that EXOSC10 can degrade both sense and antisense repeats. Furthermore, EXOSC10 reduction increased RNA foci and repeat transcripts in patient-derived cells. Cells expressing toxic poly-GR or poly-PR proteins accumulate a subset of small nucleolar RNA precursors, which are physiological substrates of EXOSC10, as well as excessive repeat RNA, indicating that arginine-rich DPR proteins impair the intrinsic activity of EXOSC10. Collectively, arginine-rich DPR-mediated impairment of EXOSC10 and the RNA exosome complex compromises repeat RNA metabolism and may thus exacerbate C9orf72-FTLD/ALS pathologies in a vicious cycle.
MeSH term(s)	Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/metabolism ; C9orf72 Protein/genetics ; C9orf72 Protein/metabolism ; Exoribonucleases/genetics ; Exoribonucleases/metabolism ; Exosome Multienzyme Ribonuclease Complex/genetics ; Exosome Multienzyme Ribonuclease Complex/metabolism ; Frontotemporal Lobar Degeneration/genetics ; Frontotemporal Lobar Degeneration/metabolism ; HeLa Cells ; Humans ; RNA/genetics ; RNA/metabolism ; RNA Stability ; Repetitive Sequences, Nucleic Acid
Chemical Substances	C9orf72 Protein ; C9orf72 protein, human ; RNA (63231-63-0) ; Exoribonucleases (EC 3.1.-) ; Exosome Multienzyme Ribonuclease Complex (EC 3.1.-) ; EXOSC10 protein, human (EC 3.1.13.-)
Language	English
Publishing date	2020-08-24
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	586044-1
ISSN	1460-2075 ; 0261-4189
ISSN (online)	1460-2075
ISSN	0261-4189
DOI	10.15252/embj.2019102700
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Article ; Online: RNA Dysmetabolism and Repeat-Associated Non-AUG Translation in Frontotemporal Lobar Degeneration/Amyotrophic Lateral Sclerosis due to

Mori, Kohji / Gotoh, Shiho / Uozumi, Ryota / Miyamoto, Tesshin / Akamine, Shoshin / Kawabe, Yuya / Tagami, Shinji / Ikeda, Manabu

JMA journal

2022 Volume 6, Issue 1, Page(s) 9–15

Abstract: Neuropathological features of frontotemporal dementia and amyotrophic lateral sclerosis (ALS) due ... ...

Abstract	Neuropathological features of frontotemporal dementia and amyotrophic lateral sclerosis (ALS) due to
Language	English
Publishing date	2022-12-23
Publishing country	Japan
Document type	Journal Article ; Review
ZDB-ID	3053329-6
ISSN	2433-3298 ; 2433-328X
ISSN (online)	2433-3298
ISSN	2433-328X
DOI	10.31662/jmaj.2022-0160
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Article ; Online: Characteristics of very late-onset schizophrenia-like psychosis classified with the biomarkers for Alzheimer's disease: a retrospective cross-sectional study.

Satake, Yuto / Kanemoto, Hideki / Taomoto, Daiki / Suehiro, Takashi / Koizumi, Fuyuki / Sato, Shunsuke / Wada, Tamiki / Matsunaga, Keiko / Shimosegawa, Eku / Gotoh, Shiho / Mori, Kohji / Morihara, Takashi / Yoshiyama, Kenji / Ikeda, Manabu

International psychogeriatrics

2023 Volume 36, Issue 1, Page(s) 64–77

Abstract: Objectives: We aimed to investigate the association between very late-onset schizophrenia-like psychosis (VLOSLP), a schizophrenia spectrum disorder with an onset of ≥60 years, and Alzheimer's disease (AD) using biomarkers.: Design: Retrospective ... ...

Abstract	Objectives: We aimed to investigate the association between very late-onset schizophrenia-like psychosis (VLOSLP), a schizophrenia spectrum disorder with an onset of ≥60 years, and Alzheimer's disease (AD) using biomarkers. Design: Retrospective cross-sectional study. Setting: Neuropsychology clinic of Osaka University Hospital in Japan. Participants: Thirty-three participants were classified into three groups: eight AD biomarker-negative VLOSLP (VLOSLP-AD), nine AD biomarker-positive VLOSLP (VLOSLP+AD), and sixteen amnestic mild cognitive impairment due to AD without psychosis (aMCI-P+AD) participants. Measurements: Phosphorylated tau levels in the cerebrospinal fluid and Results: Those in both VLOSLP-AD and +AD groups scored higher than those in aMCI-P+AD in WMS-R LM I. On the other hand, VLOSLP+AD participants scored in between the other two groups in the WMS-R LM II, with only VLOSLP-AD participants scoring significantly higher than aMCI-P+AD participants. There were no significant differences in sex distribution and MMSE scores among the three groups or in the subtype of psychotic symptoms between VLOSLP-AD and +AD participants. Four VLOSLP-AD and five VLOSLP+AD participants harbored partition delusions. Delusion of theft was shown in two VLOSLP-AD patients and five VLOSLP+AD patients. Conclusion: Some VLOSLP patients had AD pathology. Clinical characteristics were different between AD biomarker-positive and AD biomarker-negative VLOSLP, which may be helpful for detecting AD pathology in VLOSLP patients.
MeSH term(s)	Humans ; Schizophrenia/diagnosis ; Alzheimer Disease/psychology ; Cross-Sectional Studies ; Retrospective Studies ; Psychotic Disorders/diagnosis ; Psychotic Disorders/psychology ; Cognitive Dysfunction/psychology ; Biomarkers ; Amyloid beta-Peptides/cerebrospinal fluid
Chemical Substances	Biomarkers ; Amyloid beta-Peptides
Language	English
Publishing date	2023-01-30
Publishing country	England
Document type	Journal Article
ZDB-ID	1038825-4
ISSN	1741-203X ; 1041-6102
ISSN (online)	1741-203X
ISSN	1041-6102
DOI	10.1017/S1041610222001132
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Article ; Online: Cerebrospinal fluid amyloid beta with amyloid positron emission tomography concordance rates in a heterogeneous group of patients including late-onset psychotic disorders: a retrospective cross-sectional study.

Satake, Yuto / Kanemoto, Hideki / Gotoh, Shiho / Akamine, Shoshin / Suehiro, Takashi / Matsunaga, Keiko / Shimosegawa, Eku / Yoshiyama, Kenji / Morihara, Takashi / Mori, Kohji / Ikeda, Manabu

Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society

2023 Volume 23, Issue 6, Page(s) 1091–1093

MeSH term(s)	Humans ; Amyloid beta-Peptides/cerebrospinal fluid ; Cross-Sectional Studies ; Retrospective Studies ; Tomography, X-Ray Computed ; Alzheimer Disease/diagnostic imaging ; Positron-Emission Tomography/methods ; Psychotic Disorders/diagnostic imaging ; tau Proteins/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Peptide Fragments/cerebrospinal fluid
Chemical Substances	Amyloid beta-Peptides ; tau Proteins ; Biomarkers ; Peptide Fragments
Language	English
Publishing date	2023-09-12
Publishing country	England
Document type	Journal Article
ZDB-ID	2213105-X
ISSN	1479-8301 ; 1346-3500
ISSN (online)	1479-8301
ISSN	1346-3500
DOI	10.1111/psyg.13024
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Article ; Online: A heterozygous splicing variant IVS9-7A > T in intron 9 of the MAPT gene in a patient with right-temporal variant frontotemporal dementia with atypical 4 repeat tauopathy.

Mori, Kohji / Shigenobu, Kazue / Beck, Goichi / Uozumi, Ryota / Satake, Yuto / Suzuki, Maki / Kondo, Shizuko / Gotoh, Shiho / Yonenobu, Yuki / Kawai, Makiko / Suzuki, Yuki / Saito, Yuko / Morii, Eiichi / Hasegawa, Masato / Mochizuki, Hideki / Murayama, Shigeo / Ikeda, Manabu

Acta neuropathologica communications

2023 Volume 11, Issue 1, Page(s) 130

Abstract: Right temporal variant frontotemporal dementia, also called right-predominant semantic dementia, often has an unclear position within the framework of the updated diagnostic criteria for behavioral variant frontotemporal dementia or primary progressive ... ...

Abstract	Right temporal variant frontotemporal dementia, also called right-predominant semantic dementia, often has an unclear position within the framework of the updated diagnostic criteria for behavioral variant frontotemporal dementia or primary progressive aphasia. Recent studies have suggested that this population may be clinically, neuropathologically, and genetically distinct from those with behavioral variant frontotemporal dementia or left-predominant typical semantic variant primary progressive aphasia. Here we describe a Japanese case of right temporal variant frontotemporal dementia with novel heterozygous MAPT mutation Adenine to Thymidine in intervening sequence (IVS) 9 at position -7 from 3' splicing site of intron 9/exon 10 boundary (MAPT IVS9-7A > T). Postmortem neuropathological analysis revealed a predominant accumulation of 4 repeat tau, especially in the temporal lobe, amygdala, and substantia nigra, but lacked astrocytic plaques or tufted astrocytes. Immunoelectron microscopy of the tau filaments extracted from the brain revealed a ribbon-like structure. Moreover, a cellular MAPT splicing assay confirmed that this novel variant promoted the inclusion of exon 10, resulting in the predominant production of 4 repeat tau. These data strongly suggest that the MAPT IVS9-7 A > T variant found in our case is a novel mutation that stimulates the inclusion of exon 10 through alternative splicing of MAPT transcript and causes predominant 4 repeat tauopathy which clinically presents as right temporal variant frontotemporal dementia.
MeSH term(s)	Humans ; Aphasia, Primary Progressive/pathology ; Frontotemporal Dementia/genetics ; Frontotemporal Dementia/pathology ; Introns/genetics ; Mutation ; Pick Disease of the Brain/pathology ; tau Proteins/genetics ; tau Proteins/metabolism ; Tauopathies/genetics ; Tauopathies/pathology ; Temporal Lobe/metabolism
Chemical Substances	MAPT protein, human ; tau Proteins
Language	English
Publishing date	2023-08-10
Publishing country	England
Document type	Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-023-01629-3
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Article ; Online: The porphyrin TMPyP4 inhibits elongation during the noncanonical translation of the FTLD/ALS-associated GGGGCC repeat in the C9orf72 gene.

Mori, Kohji / Gotoh, Shiho / Yamashita, Tomoko / Uozumi, Ryota / Kawabe, Yuya / Tagami, Shinji / Kamp, Frits / Nuscher, Brigitte / Edbauer, Dieter / Haass, Christian / Nagai, Yoshitaka / Ikeda, Manabu

The Journal of biological chemistry

2021 Volume 297, Issue 4, Page(s) 101120

Abstract: ... GGGGCC ( ... ...

Abstract	GGGGCC (G
MeSH term(s)	Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/metabolism ; C9orf72 Protein/biosynthesis ; C9orf72 Protein/genetics ; DNA Repeat Expansion ; Frontotemporal Lobar Degeneration/genetics ; Frontotemporal Lobar Degeneration/metabolism ; HeLa Cells ; Humans ; Models, Biological ; Peptide Chain Elongation, Translational/drug effects ; Polyribosomes/metabolism ; Porphyrins/pharmacology
Chemical Substances	C9orf72 Protein ; C9orf72 protein, human ; Porphyrins ; tetra(4-N-methylpyridyl)porphine (38673-65-3)
Language	English
Publishing date	2021-08-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2021.101120
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Article ; Online: Plasma NfL is associated with mild cognitive decline in patients with diabetes.

Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society

2022 Volume 22, Issue 3, Page(s) 353–359

Abstract: Background: Patients with diabetes are at a higher risk for cognitive decline. Thus, biomarkers that can provide early and simple detection of cognitive decline are required. Neurofilament light chain (NfL) is a cytoskeletal protein that constitutes ... ...

Abstract	Background: Patients with diabetes are at a higher risk for cognitive decline. Thus, biomarkers that can provide early and simple detection of cognitive decline are required. Neurofilament light chain (NfL) is a cytoskeletal protein that constitutes neural axons. Plasma NfL levels are elevated when neurodegeneration occurs. Here, we investigated whether plasma NfL levels were associated with cognitive decline in patients with type 2 diabetes. Method: This study included 183 patients with type 2 diabetes who visited Osaka University Hospital. All participants were tested for cognitive function using the Mini-Mental State Examination (MMSE) and the Rivermead Behavioural Memory Test (RBMT). NfL levels were analysed in the plasma and the relationship between NfL and cognitive function was examined. Results: Lower RBMT-standardized profile scores (SPS) or MMSE scores correlated with higher plasma NfL levels (one-way analysis of variance: MMSE, P = 0.0237; RBMT-SPS, P = 0.0001). Furthermore, plasma NfL levels (β = -0.34, P = 0.0005) and age (β = -0.19, P = 0.016) were significantly associated with the RBMT score after multivariable regression adjustment. Conclusions: Plasma NfL levels were correlated with mild cognitive decline which is detected by the RBMT but not the MMSE in patients with type 2 diabetes. This suggests that plasma NfL levels may provide a valuable clinical tool for identifying mild cognitive decline in patients with diabetes.
MeSH term(s)	Alzheimer Disease ; Biomarkers ; Cognition ; Cognitive Dysfunction/psychology ; Diabetes Mellitus, Type 2/complications ; Humans ; Mental Status and Dementia Tests
Chemical Substances	Biomarkers
Language	English
Publishing date	2022-03-13
Publishing country	England
Document type	Journal Article
ZDB-ID	2213105-X
ISSN	1479-8301 ; 1346-3500
ISSN (online)	1479-8301
ISSN	1346-3500
DOI	10.1111/psyg.12819
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