Gen Shiihashi

RIKEN Center for Brain Science

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Field

The questionnaire survey regarding the impact of COVID-19 pandemic on Parkinson’s disease patients

Rinsho Shinkeigaku (2021)

Toshiki Tezuka Takashi Osada Yasuo Terayama Masahito Kubota Shohei Okusa

新型コロナウイルス流行によるパーキンソン病(Parkinson's disease,以下PDと略記)患者の生活への影響や医療現場への要望を調査すべく,PD患者を対象に多施設でアンケート調査を実施した.流行に伴う不安,問題,医療現場への要望を,主にオープン形式で質問し,258名から回答を得た.不安としてはPDがあると感染・重症化しやすいのではないかというものが多く,問題としてはリハビリ等に行けなくなったという回答が多かった.要望としては,電話診療を希望する意見が多かったが,対面診療を希望する声も一定数得られた.薬の宅配,電話相談窓口の設置,自宅でできるリハビリ資材を希望する意見が多かった.PD患者の不安・問題・要望に合わせた医療が求められる.

Pandemic

Computer-assisted web interviewing

Questionnaire

10.5692/clinicalneurol.cn-001663

Cite

Citations (2)

An isogenic panel of single App knock-in mouse models of Alzheimer’s disease confers differential profiles of β-secretase inhibition and endosomal abnormalities

bioRxiv (Cold Spring Harbor Laboratory) (2021)

Naoto Watamura Kaori Sato Gen Shiihashi Ayami Iwasaki Naoko Kamano

SUMMARY We previously developed single App knock-in mouse models of Alzheimer’s disease (AD) that harbor the Swedish and Beyreuther/Iberian mutations with or without the Arctic mutation ( App NL- G-F and App NL-F mice). These models showed the development of amyloid β peptide (Aβ) pathology, neuroinflammation and cognitive impairment with aging. We have now generated App knock-in mice devoid of the Swedish mutations ( App G-F mice) and some additional mutants to address the following two questions: [1] Do the Swedish mutations influence the mode of β-secretase inhibitor action in vivo ? [2] Does the quantity of C-terminal fragment of amyloid precursor protein (APP) generated by β-secretase (CTF-β) affect endosomal properties as previously reported as well as other pathological events? Aβ pathology was exhibited by App G-F mice from 6 to 8 months of age, and was accompanied by microglial and astrocyte activation. We found that a β-secretase inhibitor, verubecestat, inhibited Aβ production in App G-F mice, but not in App NL-G-F mice, indicating that the App G-F mice are more suitable for preclinical studies of β-secretase inhibition given that most AD patients do not carry Swedish mutations. We also found that the quantity of CTF-β generated by various App knock-in mutants failed to correlate with endosomal alterations or enlargement, implying that CTF-β, endosomal abnormalities, or both are unlikely to play a major role in AD pathogenesis. This is the first AD mouse model ever described that recapitulates amyloid pathology in the brain without the presence of Swedish mutations and without relying on the overexpression paradigm. Thus, experimental comparisons between different App knock-in mouse lines will potentially provide new insights into our understanding of the etiology of AD.

Gene knockin

Knockout mouse

P3 peptide

10.1101/2021.08.22.457278

Cite

Citations (1)

A novel ALS/FTD model mouse expressing cytoplasmic mutant FUS leads neurodegeneration via dendritic homeostasis disruption

Journal of the Neurological Sciences (2017)

Gen Shiihashi Daisuke Ito Iwao Arai Yuki Kobayashi Kaori Hayashi

Homeostasis

10.1016/j.jns.2017.08.231

Cite

Citations (0)

An isogenic panel of App knock-in mouse models: Profiling β-secretase inhibition and endosomal abnormalities

Science Advances (2022)

Naoto Watamura Kaori Sato Gen Shiihashi Ayami Iwasaki Naoko Kamano

We previously developed single App knock-in mouse models of Alzheimer's disease (AD) that harbor the Swedish and Beyreuther/Iberian mutations with or without the Arctic mutation (AppNL-G-F and AppNL-F mice). We have now generated App knock-in mice devoid of the Swedish mutations (AppG-F mice) and evaluated its characteristics. Amyloid β peptide (Aβ) pathology was exhibited by AppG-F mice from 6 to 8 months of age and was accompanied by neuroinflammation. Aβ-secretase inhibitor, verubecestat, attenuated Aβ production in AppG-F mice, but not in AppNL-G-F mice, indicating that the AppG-F mice are more suitable for preclinical studies of β-secretase inhibition given that most patients with AD do not carry the Swedish mutations. Comparison of isogenic App knock-in lines revealed that multiple factors, including elevated C-terminal fragment β (CTF-β) and humanization of Aβ might influence endosomal alterations in vivo. Thus, experimental comparisons between different isogenic App, knock-in mouse lines will provide previously unidentified insights into our understanding of the etiology of AD.

Gene knockin

Knockout mouse

10.1126/sciadv.abm6155

Cite

Citations (16)

Serial changes of corticospinal tract hyperintensity on magnetic resonance imaging from the preclinical stage in amyotrophic lateral sclerosis

Neurology and Clinical Neuroscience (2017)

Tsubasa Takizawa Gen Shiihashi Junki Maehara Koichi Oki Mayuko Osaka

Corticospinal tract

Pyramidal tracts

10.1111/ncn3.12165

Cite

Citations (1)

Mislocated FUS is sufficient for gain-of-toxic-function amyotrophic lateral sclerosis phenotypes in mice

Brain (2016)

Gen Shiihashi Daisuke Ito Takuya Yagi Yoshihiro Nihei Taeko Ebine

Mutations in RNA-binding proteins, including fused in sarcoma (FUS) and TAR DNA-binding protein 43 (TDP-43, encoded by TARDBP), are associated with sporadic and familial amyotrophic lateral sclerosis. A major question is whether neuronal loss is caused by toxic gain-of-function cytoplasmic aggregates or loss of nuclear RNA-binding protein function. We generated a transgenic mouse overexpressing exogenous FUS without a nuclear localization signal (ΔNLS-FUS), which developed progressive spastic motor deficits and neuronal loss in the motor cortex. The ΔNLS-FUS protein was restricted to the cytoplasm and formed ubiquitin/p62-positive aggregates. Endogenous FUS expression, nuclear localization, and splicing activity were not altered, indicating that mislocated FUS is sufficient for proteinopathy. Crossing ΔNLS-FUS with wild-type human TDP-43 transgenic mice exacerbated pathological and behavioural phenotypes, suggesting that both proteins are involved in a common cascade. RNA-sequence analysis revealed specific transcriptome alterations, including genes regulating dynein-associated molecules and endoplasmic reticulum stress. ΔNLS-FUS mice are promising tools for understanding amyotrophic lateral sclerosis pathogenesis and testing new therapeutic approaches.

TARDBP

10.1093/brain/aww161

Cite

Citations (67)

Enlargement of thymoma triggers overlapping autoimmune diseases

Autoimmunity Reviews (2016)

Gen Shiihashi Yuko Kaneko Shigeaki Suzuki Hironari Hanaoka Jin Nakahara

10.1016/j.autrev.2016.04.008

Cite

Citations (3)

Dendritic Homeostasis Disruption in a Novel Frontotemporal Dementia Mouse Model Expressing Cytoplasmic Fused in Sarcoma

EBioMedicine (2017)

Gen Shiihashi Daisuke Ito Itaru Arai Yuki Kobayashi Kanehiro Hayashi

Cytoplasmic aggregation of fused in sarcoma (FUS) is detected in brain regions affected by amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which compose the disease spectrum, FUS proteinopathy. To understand the pathomechanism of ALS-FTD-associated FUS, we examined the behavior and cellular properties of an ALS mouse model overexpressing FUS with nuclear localization signal deletion. Mutant FUS transgenic mice showed hyperactivity, social interactional deficits, and impaired fear memory retrieval, all of which are compatible with FTD phenotypes. Histological analyses showed decreased dendritic spine and synaptic density in the frontal cortex before neuronal loss. Examination of cultured cells confirmed that mutant but not wild-type FUS was associated with decreased dendritic growth, mRNA levels, and protein synthesis in dendrites. These data suggest that cytoplasmic FUS aggregates impair dendritic mRNA trafficking and translation, in turn leading to dendritic homeostasis disruption and the development of FTD phenotypes.

10.1016/j.ebiom.2017.09.005

Cite

Citations (23)