Plessis-Belair, J. | bioRxiv Science

bioRxiv2024

Importin-β specific nuclear transport defects recapitulate phenotypic and transcriptional alterations seen in neurodegeneration

Defects in Nucleocytoplasmic transport have been implicated as an important neurodegenerative pathway in ALS/FTD. Here, we show that a NemfR86S mutation results in the disruption of NCT both in vitro and in vivo. These disruptions are specific to Importin-{beta} nuclear import, and result in the nuclear loss and cytoplasmic gain of NEMF, Importin-{beta}, and TDP-43. We show that a transient nuclear import block is capable of inducing the mis-localization of TDP-43 and is associated with altered transcriptional expression of ALS, FTD, and AD/ARD genes. Taken together, these findings show that disrupted Importin-{beta} nuclear import, whether through genetic forms such as Nemf mutations, or through pharmacological inhibition, is the primary driver of TDP-43 pathology, disease-related transcriptional alterations, and neurodegeneration.

neuroscience↗

bioRxiv2023

The SATB1-MIR22-GBA axis mediates glucocerebroside accumulation inducing a cellular senescence-like phenotype in dopaminergic neurons

Idiopathic Parkinsons Disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, which is associated with neuroinflammation and reactive gliosis. The underlying cause of PD and the concurrent neuroinflammation are not well understood. In this study, we utilized human and murine neuronal lines, stem cell-derived dopaminergic neurons, and mice to demonstrate that three previously identified genetic risk factors for PD, namely SATB1, MIR22HG, and GBA, are components of a single gene regulatory pathway. Our findings indicate that dysregulation of this pathway leads to the upregulation of glucocerebrosides (GluCer), which triggers a cellular senescence-like phenotype in dopaminergic neurons. Specifically, we discovered that downregulation of the transcriptional repressor SATB1 results in the derepression of the microRNA miR-22-3p, leading to decreased GBA expression and subsequent accumulation of GluCer. Furthermore, our results demonstrate that an increase in GluCer alone is sufficient to impair lysosomal and mitochondrial function, thereby inducing cellular senescence dependent on S100A9 and stress factors. Dysregulation of the SATB1-MIR22-GBA pathway, observed in both PD patients and normal aging, leads to lysosomal and mitochondrial dysfunction due to the GluCer accumulation, ultimately resulting in a cellular senescence-like phenotype in dopaminergic neurons. Therefore, our study highlights a novel pathway involving three genetic risk factors for PD and provides a potential mechanism for the senescence-induced neuroinflammation and reactive gliosis observed in both PD and normal aging.

neuroscience↗