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.

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.

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). We have now generated App knock-in mice devoid of the Swedish mutations ( App G-F mice) and evaluated its characteristics. Amyloid β peptide (Aβ) pathology was exhibited by App G-F mice from 6 to 8 months of age and was accompanied by neuroinflammation. Aβ-secretase inhibitor, verubecestat, attenuated 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 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.

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We conducted the multicenter questionnaire survey targeting patients with Parkinson's disease (PD) in order to investigate the impacts on their daily lives and their requests to hospitals in the pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Mainly using open-ended questionnaire, we asked their anxiety, troubles they are facing, and requests toward hospitals in the pandemic of SARS-CoV-2. Two hundred fifth-eight PD patients answered the questionnaire. There were various opinions about anxiety such as "PD patients are susceptible and vulnerable to SARS-CoV-2" (36.8%). Concerning the troubles in the pandemic, the most frequent answer was that they couldn't participate in the rehabilitation and elderly day care (38.4%). Relatively many PD patients requested telemedicine (29.5%), whereas some people hoped face-to-face medical care (8.1%). There were demands about the delivery of medications (50.0%), the establishment of telephone consultations (43.8%), resources for rehabilitation at home (43.8%). The medical care adapted to the anxiety, trouble and requests of PD patients will be required in the era when we have to live with SARS-CoV-2.