Biology subjects

Ichimura, Y.

Publications and source records attributed to Ichimura, Y..

4 recordsLinked to original sources

bioRxiv2024

Loss of SPNS1, a lysosomal transporter, in the nervous system causes dysmyelination and white matter dysplasia

Protein spinster homolog 1 (SPNS1) is a lysosomal transporter of lysophospholipids and sphingosine, which has recently been identified to be mutated in patients with neurodegeneration. However, its physiological role, especially in the nervous system, remains largely unknown. In this study, we generated, for the first time, nervous system-specific Spns1 knockout mice, Spns1flox/flox;nestin-Cre, and found that the mutant mice develop neurological symptoms, such as epilepsy, and growth retardation, and die by 5 weeks of age. The mutant mice exhibited dysmyelination and oligodendrocyte shedding, while maintaining the neurons. Mutant mouse brains showed accumulation of lysophospholipids, predominantly in regions, such as the olfactory bulb and hippocampus. Furthermore, whereas sphingosine accumulated in the mutant mouse brain, the levels of ceramide and sphingoglycolipids, which are the main myelin components, were decreased. Our findings imply that abnormal sphingosine metabolism causes dysmyelination and white matter dysplasia in brain-specific Spns1-knockout mice, and indicate a possible role of SPNS1 mutation in the pathogenesis of congenital cerebral white matter dysplasia in humans.

cell biology↗

bioRxiv2022

Phosphorylation of phase-separated p62 bodies by ULK1 activates a redox-independent stress response

NRF2 is a transcription factor responsible for antioxidant stress responses that is usually regulated in a redox-dependent manner. p62 bodies formed by liquid-liquid phase separation contain Ser349-phosphorylated p62, which participates in the redox-independent activation of NRF2. However, the regulatory mechanism and physiological significance of phosphorylation remain unclear. Herein, we identify ULK1 as a kinase responsible for phosphorylation of p62. ULK1 co-localizes with p62 bodies, and directly interacts with p62. This phosphorylation allows KEAP1 to be retained within p62 bodies, activating NRF2. p62S351E/+ mice are phosphomimetic knock-in mice in which Ser351 corresponding to human Ser349 is replaced by Glu. These mice, but not phosphodefective p62S351A/S351A mice, exhibit NRF2 hyperactivation and growth retardation, the latter caused by malnutrition and dehydration due to obstruction of the esophagus and forestomach secondary to hyperkeratosis. p62S351E/+ mice are a phenocopy of systemic Keap1-knockout mice. Our results expand our understanding of the physiological importance of the redox-independent NRF2 activation pathway and provide new insight into the role of phase separation in this process.

cell biology↗

bioRxiv2021

Droplets of amyotrophic lateral sclerosis-associated p62/SQSTM1 mutants show slower inner fluidity

A series of amyotrophic lateral sclerosis (ALS)-related proteins such as FUS, TDP-43 and hnRNPA1 has an ability to be liquid-liquid phase separation, and their disease-related mutations cause the transition of their responsible liquid droplets to aggregates. Missense mutations in SQSTM1/p62, which have been identified throughout the gene, are associated with ALS, frontotemporal degeneration (FTD) and Pagets disease of bone. SQSTM1/p62 protein forms liquid-droplets through the interaction with ubiquitinated proteins, and the droplet serves as a platform of autophagosome formation and anti-oxidative stress response via the LC3-interacting region (LIR) and Keap1-interacting region (KIR), respectively. However, it remains unclear whether ALS/FTD-related p62 mutations in LIR and KIR form aberrant liquid droplets, cause defective autophagy and stress response or both. To evaluate the effects of ALS/FTD-related p62 mutations in LIR and KIR on a major oxidative stress system, the Keap1-Nrf2 pathway and the autophagic turnover, we developed systems that enable to monitor them with high sensitivity. These systems revealed that some mutants but not all have their less abilities on the Nrf2-activation and show the delayed turnover. By contrast, while the sufficient ability to form liquid droplets, all droplets consisting of p62 mutants showed slower inner fluidity. These results indicate that like other ALS-related mutant proteins, a primary defect in ALS/FTD with p62 missense mutations is a qualitative change of p62-liquid droplets.

cell biology↗

bioRxiv2020

Resting-state functional connectivity predicts recovery from visually induced motion sickness

Movies depicting certain types of motion often provoke uncomfortable symptoms similar to motion sickness, termed visually induced motion sickness (VIMS). VIMS generally evolves slowly during the viewing of a motion stimulus and, when the stimulus is removed, the recovery proceeds over time. Recent human neuroimaging studies have provided new insights into the neural bases underlying the evolution of VIMS. In contrast, no study has investigated the neural bases underlying the recovery from VIMS. Study of the recovery process is critical for the development of a way to promote recovery and could provide further clues for understanding the mechanisms of VIMS. We thus investigated brain activity during the recovery from VIMS with functional connectivity (FC) magnetic resonance imaging. We found enhanced recovery-related FC patterns involving brain areas such as the insular, cingulate, and visual cortical regions, which have been suggested to play important roles in the emergence of VIMS. These regions also constituted large interactive networks. Furthermore, the increase in FC was correlated with the subjective awareness of recovery for the following 5 pairs of brain regions: insula-superior temporal gyrus, claustrum-left and right inferior parietal lobules, claustrum-superior temporal gyrus, and superior frontal gyrus-lentiform nucleus. Considering the previous findings on the functions of these regions and the present findings, it is suggested that the increase in FC may reflect brain processes such as enhanced interoceptive awareness to ones own bodily state, a neuroplastic change in visual processing circuits, and/or the maintenance of visual spatial memory.

neuroscience↗