Sonlicromanol improves neuronal network dysfunction and transcriptome changes linked to m.3243A>G heteroplasmy in...

Area of Science:

• Neuroscience
• Genetics
• Mitochondrial Biology

Background:

• Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a genetic disorder.
• The m.3243A>G variant in the MT-TL1 gene is a common cause of MELAS.
• Understanding the impact of this variant on neuronal function is crucial for developing treatments.

Purpose of the Study:

• To investigate the effects of the m.3243A>G MELAS variant on human iPSC-derived excitatory neurons.
• To identify transcriptomic changes associated with mitochondrial dysfunction in these neurons.
• To evaluate the therapeutic potential of sonlicromanol in a preclinical MELAS model.

Main Methods:

• Generation of human induced pluripotent stem cells (iPSCs) from MELAS patients with varying heteroplasmy levels of the m.3243A>G variant.
• Differentiation of iPSCs into excitatory neurons and co-culture with astrocytes.
• Micro-electrode array (MEA) recordings for neuronal network activity assessment.
• RNA sequencing (MEA-seq) to analyze transcriptomic profiles.
• Treatment with sonlicromanol at an early developmental stage.

Main Results:

• Neurons with high m.3243A>G heteroplasmy exhibited reduced expression of genes involved in mitochondrial respiration and presynaptic function.
• Non-cell autonomous processes in co-cultured astrocytes were also affected.
• Early sonlicromanol treatment improved neuronal network activity and modulated the neuronal transcriptome.
• The observed pathology was partially reversible with sonlicromanol intervention.

Conclusions:

• The m.3243A>G MELAS variant induces significant transcriptomic alterations in iPSC-derived neurons, impacting mitochondrial function and neuronal communication.
• Astrocytes play a non-cell autonomous role in the disease pathology.
• Sonlicromanol demonstrates therapeutic potential by improving neuronal function and partially reversing disease-associated transcriptomic changes when administered early.