Signs of early cellular dysfunction in multiple system atrophy.

AIMS: Multiple system atrophy (MSA) is a fatal neurodegenerative disease that belongs to the family of α-synucleinopathies. At post mortem examination, intracellular inclusions of misfolded α-synuclein are found in neurons and oligodendrocytes and are considered to play a significant role in the pathogenesis. However, the early steps of the disease process are unknown and difficult to study in tissue derived from end-stage disease. METHODS: Induced pluripotent stem cells (iPSCs) were generated from patients' and control skin fibroblasts and differentiated into NCAM-positive neural progenitor cells (NPCs). The mitochondrial morphology and function were assessed by immunocytochemistry and high resolution respirometry. The ability to cope with exogenous oxidative stress was tested by exposure to different doses of luperox. The expression of α-synuclein was studied by immunocytochemistry. RESULTS: We identified increased tubulation of mitochondria with preserved respiration profile in MSA-derived NPCs. Exposure of these cells to exogenous oxidative stress even at low doses, triggered an excessive generation of reactive oxygen species (ROS) and cleavage of caspase-3. MSA-derived NPCs did not present changed levels of SNCA gene expression nor intracellular aggregates of α-synuclein. However, we identified disease-related translocation of α-synuclein to the nucleus. CONCLUSIONS: Our results show early cellular dysfunction in MSA-derived NPCs. We identified changes in the redox homeostasis which are functionally compensated at baseline but cause increased susceptibility to exogenous oxidative stress. In addition, nuclear translocation of α-synuclein in MSA-derived NPCs supports an early cellular stress response which may precede the neurodegenerative process in this disorder.

Transcriptomic insights into multiple system atrophy from a PLP-α-synuclein transgenic mouse model.

Multiple system atrophy (MSA) is a rare, neurodegenerative disorder with rapid motor and non-motor symptom progression. MSA is characterized by protein aggregations of α-synuclein found in the cytoplasm of oligodendrocytes. Despite this pathological hallmark, there is still little known about the cause of this disease, resulting in poor treatment options and quality of life post-diagnosis. In this study, we investigated differentially expressed genes (DEGs) via RNA-sequencing of brain samples from a validated PLP-α-synuclein transgenic mouse model, identifying a total of 40 DEGs in the PLP group compared to wild-type (WT), with top detected genes being Gm15446, Mcm6, Aldh7a1 and Gm3435. We observed a significant enrichment of immune pathways and endothelial cell genes among the upregulated genes, whereas downregulated genes were significantly enriched for oligodendrocyte and neuronal genes. We then calculated possible overlap of these DEGs with previously profiled human MSA RNA, resulting in the identification of significant downregulation of the Tsr2 gene. Identifying key gene expression profiles specific to MSA patients is crucial to further understanding the cause, and possible prevention, of this rapidly progressive neurodegenerative disorder.