Language
English
Publication Date
4-1-2024
Journal
Aging Cell
DOI
10.1111/acel.14077
PMID
38303548
PMCID
PMC11019121
PubMedCentral® Posted Date
2-1-2023
PubMedCentral® Full Text Version
Post-print
Abstract
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.
Keywords
Humans, Mice, Animals, Dopaminergic Neurons, Matrix Attachment Region Binding Proteins, Glucosylceramides, Gliosis, Neuroinflammatory Diseases, Parkinson Disease, MicroRNAs, Cellular Senescence, Transcription Factors, Phenotype, gene expression regulation, glucosylceramides, lysosomes, MicroRNAs, mitochondria, neuroinflammation, Parkinson's disease, senescence
Published Open-Access
yes
Recommended Citation
Russo, Taylor; Kolisnyk, Benjamin; B S, Aswathy; et al., "The SATB1-MIR22-Gba Axis Mediates Glucocerebroside Accumulation Inducing a Cellular Senescence-Like Phenotype in Dopaminergic Neurons" (2024). Faculty, Staff and Students Publications. 6219.
https://digitalcommons.library.tmc.edu/baylor_docs/6219