Signs of early cellular dysfunction in multiple system atrophy

Area of Science:

• Neurodegenerative diseases
• α-synucleinopathies
• Cellular biology

Background:

• Multiple system atrophy (MSA) is a fatal neurodegenerative disease linked to α-synuclein.
• Intracellular α-synuclein aggregates are implicated in pathogenesis, but early disease mechanisms remain unclear.
• Studying early disease stages is challenging due to reliance on end-stage tissue.

Purpose of the Study:

• To investigate early cellular dysfunction in Multiple System Atrophy (MSA) using patient-derived cells.
• To assess mitochondrial function and response to oxidative stress in MSA neural progenitor cells (NPCs).
• To examine α-synuclein expression and localization in early-stage MSA models.

Main Methods:

• Generated induced pluripotent stem cells (iPSCs) from MSA patients and controls.
• Differentiated iPSCs into neural progenitor cells (NPCs).
• Assessed mitochondrial morphology/function, oxidative stress response, and α-synuclein expression/localization.

Main Results:

• MSA-derived NPCs showed increased mitochondrial tubulation but preserved respiration.
• Exposure to oxidative stress induced excessive reactive oxygen species (ROS) and caspase-3 cleavage in MSA NPCs.
• Nuclear translocation of α-synuclein was observed in MSA NPCs, without altered SNCA gene expression or intracellular aggregates.

Conclusions:

• MSA-derived NPCs exhibit early cellular dysfunction, including altered redox homeostasis.
• Cells are compensated at baseline but show increased susceptibility to exogenous oxidative stress.
• Nuclear α-synuclein translocation indicates an early cellular stress response preceding neurodegeneration in MSA.