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

  • Commun Biol. 2024 Oct 1;7(1):1227. doi: 10.1038/s42003-024-06896-x.
Borui Zhang  #  1 ,  Kai Chen  #  1 ,  Yelin Dai  1 ,  Xi Luo  1 ,  Ziwei Xiong  #  1 ,  Weijia Zhang  1 ,  Xiaodan Huang  1 ,  Kwok-Fai So  1  2  3  4  5 ,  Li Zhang  6  7  8  9
Affiliations
  • 1. Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, P. R. China.
  • 2. State Key Laboratory of Brain and Cognitive Science, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P. R. China.
  • 3. Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, Guangzhou, P. R. China.
  • 4. Neuroscience and Neurorehabilitation Institute, University of Health and Rehabilitation Sciences, Qingdao, China.
  • 5. Center for Exercise and Brain Science, School of Psychology, Shanghai University of Sport, Shanghai, China.
  • 6. Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, P. R. China. [email protected].
  • 7. Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, Guangzhou, P. R. China. [email protected].
  • 8. Neuroscience and Neurorehabilitation Institute, University of Health and Rehabilitation Sciences, Qingdao, China. [email protected].
  • 9. Center for Exercise and Brain Science, School of Psychology, Shanghai University of Sport, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 39349708 DOI: 10.1038/s42003-024-06896-x
Abstract

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.

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