Human α-synuclein aggregation activates ferroptosis leading to parvalbumin interneuron degeneration and motor learning impairment.

The accumulation of α-synuclein induces neuronal loss in midbrain nuclei and leads to the disruption of motor circuits, while the pathology of α-synuclein in cortical regions remains elusive. To better characterize cortical synucleinopathy, here we generate a mouse model with the overexpression of human α-synuclein in the primary motor cortex (M1) of mice. A combination of molecular, in vivo recording, and behavioral approaches reveal that cortical expression of human α-synuclein results in the overexcitation of cortical pyramidal neurons (PNs), which are regulated by the decreased inhibitory inputs from parvalbumin-interneurons (PV-INs) to impair complex motor skill learning. Further mechanistic dissections reveal that human α-synuclein aggregation activates ferroptosis, contributing to PV-IN degeneration and motor circuit dysfunction. Taken together, the current study adds more knowledge to the emerging role and pathogenic mechanism of ferroptosis in neurodegenerative diseases.