CDR1as regulates α-synuclein-mediated ischemic brain damage by controlling miR-7 availability

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Transient focal ischemia reduces microRNA-7 (miR-7) levels, leading to increased alpha-synuclein (α-Syn) and secondary brain damage.
• Circular RNA CDR1as regulates miR-7 abundance and function, suggesting a role in ischemic stroke.

Purpose of the Study:

• To investigate the functional significance of CDR1as in focal cerebral ischemia.
• To evaluate the neuroprotective effects of CDR1as reconstitution after stroke.

Main Methods:

• Transient middle cerebral artery occlusion (MCAO) model in adult mice.
• Intracerebral injection of an adeno-associated virus serotype 9 (AAV9) vector carrying the CDR1as gene.
• Measurement of CDR1as, miR-7, and α-Syn levels, infarct size, apoptosis, autophagy, and inflammation markers.
• Assessment of motor function recovery.

Main Results:

• MCAO significantly downregulated CDR1as and miR-7 in the peri-infarct cortex.
• AAV9-mediated CDR1as overexpression increased miR-7 levels and CDR1as binding to Ago2/miR-7.
• CDR1as overexpression suppressed α-Syn induction, reduced infarct size, decreased apoptosis, autophagy, and inflammation, and promoted motor function recovery.

Conclusions:

• CDR1as reconstitution demonstrates significant neuroprotective effects in a mouse model of ischemic stroke.
• CDR1as likely exerts its protective effects by preserving miR-7 and inhibiting α-Syn-mediated neuronal death.
• CDR1as represents a potential therapeutic target for stroke treatment.