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

Idiopathic Parkinson's 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 utilize 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. 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. Overview of the SATB1-MIR22HG-GBA-GluCer pathway. The senescence regulator SATB1 acts as a negative regulator of MIR22HG expression. Decreased SATB1 levels lead to increased MIR22HG expression. Following nuclear processing, miR-22-3p targets GBA mRNA, reducing its transcription. This results in reduced GCase activity and the consequent accumulation of its substrate GluCer, a cerebroside that impairs mitochondrial and lysosomal function. GluCer accumulation leads to elevated ROS production and increased Cdkn1a (p21), Cdkn2a (p16) and S100A9 expression, ultimately driving cellular senescence. Importantly, the genes SATB1, MIR22HG, and GBA (red stars) are associated with Parkinson's disease. During aging, SATB1 and GBA levels decrease (red hourglasses), while MIR22HG, GluCer, p21/p16, and ROS levels increase (green hourglasses), rendering DA neurons more vulnerable.image