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.
['Herrera-Vaquero|M|M|', 'Heras-Garvin|A|A|0000-0003-2231-2681', 'Krismer|F|F|', 'Deleanu|R|R|', 'Boesch|S|S|', 'Wenning|G K|GK|', 'Stefanova|N|N|0000-0001-8188-639X']
D002478:Cells, Cultured D006801:Humans D057026:Induced Pluripotent Stem Cells D008928:Mitochondria D019578:Multiple System Atrophy D058953:Neural Stem Cells D018384:Oxidative Stress D021381:Protein Transport D051844:alpha-Synuclein
multiple system atrophy α-synuclein induced pluripotent stem cells high resolution respirometry oxidative stress mitochondria