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  3. Reduced lysosomal density in neuronal dendrites mediates deficits in synaptic plasticity in Huntington's disease

Reduced lysosomal density in neuronal dendrites mediates deficits in synaptic plasticity in Huntington's disease

  • Cell Rep. 2023 Dec 26;42(12):113573. doi: 10.1016/j.celrep.2023.113573.
Jia-Hui Chen 1,  Na Xu 2,  Lei Qi 3,  Hao-Hao Yan 2,  Fang-Yan Wan 2,  Feng Gao 4,  Chuanhai Fu 5,  Chunlei Cang 2,  Boxun Lu 6,  Guo-Qiang Bi 7,  Ai-Hui Tang 8
Affiliations

Affiliations

  • 1 Department of Neurology and Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China; Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei 230088, China; CAS Key Laboratory of Brain Function and Disease, MOE Key Laboratory for Membrane-less Organelles & Cellular Dynamics, Neurodegenerative Disorder Research Center and Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei 230027, China. Electronic address: chenjh95@ustc.edu.cn.
  • 2 Department of Neurology and Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China; CAS Key Laboratory of Brain Function and Disease, MOE Key Laboratory for Membrane-less Organelles & Cellular Dynamics, Neurodegenerative Disorder Research Center and Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei 230027, China.
  • 3 Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei 230088, China.
  • 4 Department of Neurology and Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China.
  • 5 CAS Key Laboratory of Brain Function and Disease, MOE Key Laboratory for Membrane-less Organelles & Cellular Dynamics, Neurodegenerative Disorder Research Center and Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei 230027, China.
  • 6 State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Huashan Hospital, School of Life Sciences, Fudan University, Shanghai 200433, China.
  • 7 Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei 230088, China; CAS Key Laboratory of Brain Function and Disease, MOE Key Laboratory for Membrane-less Organelles & Cellular Dynamics, Neurodegenerative Disorder Research Center and Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei 230027, China; Interdisciplinary Center for Brain Information, The Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Guangdong 518055, China.
  • 8 Department of Neurology and Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China; Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei 230088, China; CAS Key Laboratory of Brain Function and Disease, MOE Key Laboratory for Membrane-less Organelles & Cellular Dynamics, Neurodegenerative Disorder Research Center and Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei 230027, China. Electronic address: tangah@ustc.edu.cn.
PMID: 38096054 DOI: 10.1016/j.celrep.2023.113573
Abstract

Huntington's disease (HD) usually causes cognitive disorders, including learning difficulties, that emerge before motor symptoms. Mutations related to lysosomal trafficking are linked to the pathogenesis of neurological diseases, whereas the cellular mechanisms remain elusive. Here, we discover a reduction in the dendritic density of lysosomes in the hippocampus that correlates with deficits in synaptic plasticity and spatial learning in early CAG-140 HD model mice. We directly manipulate intraneuronal lysosomal positioning with light-induced CRY2:CIB1 dimerization and demonstrate that lysosomal abundance in dendrites positively modulates long-term potentiation of glutamatergic synapses onto the neuron. This modulation depends on lysosomal CA2+ release, which further promotes endoplasmic reticulum (ER) entry into spines. Importantly, optogenetically restoring lysosomal density in dendrites rescues the synaptic plasticity deficit in hippocampal slices of CAG-140 mice. Our data reveal dendritic lysosomal density as a modulator of synaptic plasticity and suggest a role of lysosomal mispositioning in cognitive decline in HD.

Keywords

CAG-140 mice; CP: Cell biology; CP: Neuroscience; hippocampus; light-induced dimerization; long-term potentiation; lysosome; optogenetic.

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