α-Synuclein propagation leads to synaptic abnormalities in the cortex through microglial synapse phagocytosis

Molecular Brain

Research

Dayana Pérez-Acuña¹  Soo Jean Shin¹  Ka Hyun Rhee²  Sang Jeong Kim³  Seung-Jae Lee⁴ 

[1] Department of Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-Ro, Jongro-Gu, 03080, Seoul, Republic of Korea;Department of Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-Ro, Jongro-Gu, 03080, Seoul, Republic of Korea;Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, 55455, Minneapolis, MN, USA;Department of Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-Ro, Jongro-Gu, 03080, Seoul, Republic of Korea;Department of Physiology, Seoul National University, College of Medicine, 03080, Seoul, Republic of Korea;Neuroscience Research Institute, Seoul National University College of Medicine, 03080, Seoul, Republic of Korea;Department of Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-Ro, Jongro-Gu, 03080, Seoul, Republic of Korea;Neuroscience Research Institute, Seoul National University College of Medicine, 03080, Seoul, Republic of Korea;Convergence Research Center for Dementia, Seoul National University College of Medicine, 03080, Seoul, Republic of Korea;04796, Neuramedy, Seoul, Republic of Korea;

关键词: Parkinson’s disease;    α-synuclein;    Protein aggregation;    Microglia;    Synapse degeneration;   

DOI  :  10.1186/s13041-023-01059-1

 received in 2023-08-15, accepted in 2023-09-15,  发布年份 2023

来源: Springer

【 摘 要 】

The major neuropathologic feature of Parkinson’s disease is the presence of widespread intracellular inclusions of α-synuclein known as Lewy bodies. Evidence suggests that these misfolded protein inclusions spread through the brain with disease progression. Changes in synaptic function precede neurodegeneration, and this extracellular α-synuclein can affect synaptic transmission. However, whether and how the spreading of α-synuclein aggregates modulates synaptic function before neuronal loss remains unknown. In the present study, we investigated the effect of intrastriatal injection of α-synuclein preformed fibrils (PFFs) on synaptic activity in the somatosensory cortex using a combination of whole-cell patch-clamp electrophysiology, histology, and Golgi-Cox staining. Intrastriatal PFF injection was followed by formation of phosphorylated α-synuclein inclusions in layer 5 of the somatosensory cortex, leading to a decrease in synapse density, dendritic spines, and spontaneous excitatory post-synaptic currents, without apparent neuronal loss. Additionally, three-dimensional reconstruction of microglia using confocal imaging showed an increase in the engulfment of synapses. Collectively, our data indicate that propagation of α-synuclein through neural networks causes abnormalities in synaptic structure and dynamics prior to neuronal loss.

【 授权许可】

CC BY   
© Min Zhuo, Bong-Kiun Kaang and BioMed central Ltd. 2023

【 图 表 】

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