Hioki, T. | bioRxiv Science

bioRxiv2024

Two types of regeneration mechanism in acute liver injury

The liver has a strong regenerative capacity, but the mechanisms of liver regeneration are not well understood. Furthermore, many previous studies on liver regeneration have been conducted in partial hepatectomy models, which may differ from acute liver injury with inflammation and necrosis, as observed in many clinical cases. In this study, we conducted a single-cell RNA-seq analysis (scRNA-seq) of liver regeneration in mice treated with acetaminophen (APAP) using publicly available data. We discovered that two cell proliferation populations appeared simultaneously during a single regenerative process. The two populations differed significantly in terms of differentiation, localization, proliferation rate, and signal response. Furthermore, one of the populations was induced by contact with necrotic tissue and exhibited a higher proliferative capacity with a dedifferentiated feature. These findings can shed new light on liver regeneration and aid in the development of therapeutic strategies for liver failure.

pathology↗

bioRxiv2024

AAV delivery of GBA1 suppresses alpha-synuclein accumulation in Parkinson's disease models and restores motor dysfunction in a Gaucher's disease model

Biallelic mutations in the glucosylceramidase beta 1 (GBA1) gene are the underlying genetic cause of Gauchers disease (GD), resulting in a deficient lysosomal hydrolase and subsequent accumulation of glycosphingolipids. More recently, GBA1 mutations have been identified as the most prevalent genetic risk factor for Parkinsons disease (PD), associated with more pronounced symptoms characterized by earlier onset and accelerated cognitive decline. In these GBA-associated PD patients the -synuclein pathology is more prominent, and recent data suggest a link between -synucleinopathies and GBA1 mutations. Here, we explored the effect of GBA1 gene supplementation on the GD phenotypes and -synuclein pathology by using the adeno-associated virus (AAV) system. We have compared two AAV serotypes, AAV5 and AAV9, and two different ubiquitous promoters, and demonstrate that both promoters work efficiently albeit not the same in vitro and in vivo. GBA1 overexpression reduces the accumulation of glucosylsphingosine (GlcSph) and restores motor dysfunction in a GD mouse model. We further demonstrate that GBA1 overexpression can dissolve phospho--synuclein aggregation induced by the addition of -synuclein pre-formed fibril (PFF) in a mouse primary neuron model suggesting the direct effect of {beta}-Glucocerebrosidase (GCase) on -synuclein accumulation. In vivo, we show that GCase inhibition can induce insoluble high-molecular-weight -synuclein aggregation and that delivery of GBA1 achieves robust reduction of the -synuclein aggregates in the mouse brain. In summary, GCase expression not only reduces GlcSph, but also restores GD motor dysfunction and removes -synuclein aggregates which are the hallmark for PD and -synucleinopathies. AAV delivery of GBA1 is a powerful approach to restore glucocerebrosidase function and to resolve misfolded -synuclein protein, with applications for GD and PD.

neuroscience↗