Publications by authors named "Shotaro Shimonaka"

Corticobasal degeneration (CBD) is a major four-repeat tauopathy along with progressive supranuclear palsy (PSP). Although detergent-insoluble 37-40-kDa carboxyl-terminal tau fragments (CTFs) are hallmarks of CBD pathology, the process of their formation is unknown. This study monitored the formation of CBD-type fibrils that exhibit astrocytic plaques, a characteristic CBD pathology, using its biochemical properties different from those of Alzheimer's disease/PSP-type fibrils.

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  • Current Alzheimer's disease (AD) treatments are inadequate, with tau protein aggregation correlating strongly with symptoms, highlighting the need for effective therapies targeting tau pathology.
  • A study screened 763 FDA-approved compounds for their ability to inhibit tau aggregation using AD seeds, narrowing down to 4 potential candidates, including lansoprazole as the most promising option.
  • In mice studies, intranasal administration of lansoprazole improved movement and reduced tau aggregation, suggesting its potential as a repositioned drug for treating AD.
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  • The α-Synuclein V15A variant has been linked to Parkinson's disease in two Caucasian families, but its significance was previously unclear.
  • Researchers conducted a comprehensive analysis of the variant's effects on phospholipid binding and protein aggregation in cells, discovering it to be rare and potentially pathogenic.
  • V15A showed stronger amplification of α-Syn fibrils compared to wild-type and had a lowered affinity for phospholipids, suggesting it could contribute to Parkinson's disease development.
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α-Synuclein, a presynaptic protein, is involved in synaptic vesicle dynamics in response to neuronal activity. Mutations of the α-synuclein gene and the neuronal deposition of α-synuclein, called Lewy bodies, are linked to the development of Parkinson's disease. α-Synuclein has a prion-like property that converts its physiological protein conformation to a pathogenic one, forming disease-causing fibrils.

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  • Type 2 diabetes mellitus (T2DM) is linked to an increased risk of Alzheimer's disease (AD), but the specific mechanisms connecting the two are not fully understood.
  • Researchers found that SGK1, a protein activated by a chronic high-fat diet (HFD), plays a role in promoting tau pathology, a hallmark of AD, by phosphorylating tau and activating the kinase GSK-3ß.
  • Increased levels of SGK1 in the hippocampus lead to neurodegeneration and cognitive impairments, suggesting that SGK1 connects T2DM and AD by influencing tau pathology in response to glucocorticoids and high blood sugar.
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Different conformational strains of tau have been implicated in the clinicopathological heterogeneity of tauopathies. In this study, we hypothesized that distinct strains are degraded in a different manner. Lithium, a drug for bipolar disorder, had previously been reported to reduce aggregation-prone protein content by promoting autophagy.

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Background: Human tauopathy brain injections into the mouse brain induce the development of tau aggregates, which spread to functionally connected brain regions; however, the features of this neurotoxicity remain unclear. One reason may be short observational periods because previous studies mostly used mutated-tau transgenic mice and needed to complete the study before these mice developed neurofibrillary tangles.

Objective: To examine whether long-term incubation of Alzheimer's disease (AD) brain in the mouse brain cause functional decline.

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In tauopathies, tau forms pathogenic fibrils with distinct conformations (termed "tau strains") and acts as an aggregation "seed" templating the conversion of normal tau into isomorphic fibrils. Previous research showed that the aggregation core of tau fibril covers the C-terminal region (243-406 amino acids (aa)) and differs among the diseases. However, the mechanisms by which distinct fibrous structures are formed and inherited via templated aggregation are still unknown.

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  • Variants in the MAPT gene are linked to genetic tauopathies, which are a type of frontotemporal dementia (FTD).
  • In a study of 165 cases, researchers discovered two new MAPT variants: p.P160S and p.K298_H299insQ, associated with different forms of FTD and progressive supranuclear palsy.
  • Laboratory tests showed that these variants led to abnormal behavior in tau proteins, such as reduced microtubule assembly and increased aggregation, potentially contributing to neurodegeneration.
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TAR DNA-binding protein of 43 kDa (TDP-43) has been identified as the major component of ubiquitin-positive neuronal and glial inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Aggregation of TDP-43 to amyloid-like fibrils and spreading of the aggregates are suggested to account for the pathogenesis and progression of these diseases. To investigate the molecular mechanisms of TDP-43 aggregation, we attempted to identify the amino acid sequence required for the aggregation.

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