journal article·2025-10Open access

Dynein‐Dependent Endo‐Lysosomal Degradation Drives Lewy Body Disorders Accompanied by Aβ Pathology

Linlin Zhou, Yuwei Wang, Yu Liu, Feipeng Zhu, Ge Gao, Chengjie Li, Pu Ai, Jingying Xu, Junxin Wang, Long Guo, Yuting Guan, Virginia Man‐Yee Lee, Jianjun Chen, Jialin Zheng, Qihui Wu

Advanced Science· Volume 12· Issue 37

Abstract

Abstract Dementia with Lewy bodies (DLB) is a significant cause of dementia. However, the limited availability of animal and cellular models that accurately replicate early DLB pathogenesis hampers the understanding of how Aβ plaques influence α‐synuclein (αSyn) pathologies. This study addresses this gap by co‐culturing primary neurons with adult hippocampal brain slices from either wild‐type or Alzheimer's disease (AD) mice containing abundant Aβ plaques and cytokines. Neurons exposed to AD slices showed impaired dynein‐dependent organelle trafficking, reducing endosome–lysosome fusion and causing defective degradation of amyloidogenic αSyn fibrils, thus increasing αSyn inclusions. Notably, an abnormal pre‐accumulation of dynein in AD mice suggests that dysfunctional dynein may serve as a nucleation site for αSyn aggregation upon exposure to pathogenic fibrils. Furthermore, Rab7 activation successfully restored endo‐lysosomal degradation of αSyn fibrils and reduced inclusion formation in mouse models presenting with both Lewy body and Aβ pathologies. These results highlight the dynein‐dependent endo‐lysosomal pathway as a promising therapeutic target for mitigating αSyn‐related pathologies in co‐existing Aβ burden, characteristic of many DLB cases.
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Research context

OpenAlex topics: Parkinson's Disease Mechanisms and Treatments · Alzheimer's disease research and treatments · Lysosomal Storage Disorders Research

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation Clinical Research Center for Anesthesiology and Perioperative Medicine Translational Research Institute of Brain and Brain‐Like Intelligence Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine State Key Laboratory of Cardiology and Medical Innovation Center Shanghai East Hospital School of Medicine Tongji University Shanghai 200092 China

State Key Laboratory for Molecular Developmental Biology Institute of Genetics and Developmental Biology Chinese Academy of Sciences Beijing 100101 China

Center for Translational Neurodegeneration and Regenerative Therapy Tongji Hospital affiliated to Tongji University School of Medicine Shanghai Frontiers Science Center of Nanocatalytic Medicine The Institute for Biomedical Engineering & Nano Science School of Medicine Tongji University Shanghai 200092 China

School of Medicine Tongji University 500 Zhennan Road Shanghai 200331 China

Shanghai Frontiers Science Center of Genome Editing and Cell Therapy Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences East China Normal University Shanghai 200241 China

Department of Pathology and Laboratory Medicine Institute on Aging and Center for Neurodegenerative Disease Research Perelman School of Medicine University of Pennsylvania Philadelphia PA 19104 USA

Funding

National Natural Science Foundation of China · Science and Technology Commission of Shanghai Municipality · Fundamental Research Funds for the Central Universities

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