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

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

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. zhangli@jnu.edu.cn.
  • 7 Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, Guangzhou, P. R. China. zhangli@jnu.edu.cn.
  • 8 Neuroscience and Neurorehabilitation Institute, University of Health and Rehabilitation Sciences, Qingdao, China. zhangli@jnu.edu.cn.
  • 9 Center for Exercise and Brain Science, School of Psychology, Shanghai University of Sport, Shanghai, China. zhangli@jnu.edu.cn.
  • # 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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