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Pathological and physiological functional cross-talks ofα-synuclein and tau in the central nervous system

Neural Regeneration Research 2024年第4期19卷 855-862页

作者： Mingyue Jin Shengming Wang Xiaodie Gao Zhenyou Zou shinji hirotsune Liyuan Sun Guangxi Key Laboratory of Brain and Cognitive Neuroscience Guilin Medical University Department of Genetic Disease Research Osaka Metropolitan University Graduate School of Medicine Department of Scientific Research Brain Hospital of Guangxi Zhuang Autonomous Region

α-Synuclein and tau are abundant multifunctional brain proteins that are mainly expressed in the presynaptic and axonal compartments of neurons,*** works have revealed that intracellular deposition ofα-synuclein and/or tau causes many neurodegenerative disorders,including Alzheimer’s disease and Parkinson’s *** intense investigation,the normal physiological functions and roles ofα-synuclein and tau are still unclear,owing to the fact that mice with knockout of either of these proteins do not present apparent ***,the co-occurrence ofα-synuclein and tau aggregates was found in post-mortem brains with synucleinopathies and tauopathies,some of which share similarities in clinical ***,the direct interaction ofα-synuclein with tau is considered to promote the fibrillization of each of the proteins in vitro and in *** the other hand,our recent findings have revealed thatα-synuclein and tau are cooperatively involved in brain development in a stage-dependent *** findings indicate strong cross-talk between the two proteins in physiology and *** this review,we provide a summary of the recent findings on the functional roles ofα-synuclein and tau in the physiological conditions and pathogenesis of neurodegenerative diseases.A deep understanding of the interplay betweenα-synuclein and tau in physiological and pathological conditions might provide novel targets for clinical diagnosis and therapeutic strategies to treat neurodegenerative diseases.

关键词： alpha-synuclein microtubule-associated protein neurodegenerative disease tau

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Alpha-synuclein has a unique function in axonal transport

Alpha-synuclein has a unique function in axonal transport

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中国神经科学学会第十二届全国学术会议

作者： Mingyue Jin Shiori Toba Sakiko Matsumoto shinji hirotsune Department of Genetic Disease Research Osaka City University Graduate School of Medicine

Objective Alterations in axonal transport have been implicated in neurodegeneration and its progression in a number of neurodegenerative diseases including Parkinson’s disease（PD）. Several studies already reported the involvement of α-Syn and cytoplasmic dynein in neurodegeneration, but how mutant synucleins play a causative role is not clear. In this study, we attempted to explore that how α-Syn functions in axonal transport. Methods The function of α-Syn in axonal transport was examined by live cell imaging in combination with super-resolution photo-activated localization microscopy（SR-PALM） and transmission electron microscopy. Results（1） α-Syn stabilizes short microtubules（MTs） and preferentially binds to MTs carrying 14-protofilaments（pfs） in vitro.（2） We previously proposed a daring model for a transportable microtubule（t MT）, in which dynein is anchored on a t MT by LIS1 followed by anterograde transport by kinesin-1. Live-cell imaging indicated the cotransport of α-Syn with dynein to the plus ends of MTs in neurons, which is severely affected in its mutant forms. SR-PALM further revealed fibrous co-localization of α-Syn with βIII-tubulin and dynein.（3） MTs carrying 14-pfs were found in rat femoral nerve tissue, which increased around 19-fold the control in quantify upon nerve ligation, emphasizing the unconventional 14-pfs MTs are mobile. Conclusion Here, we found a unique function of α-Syn in anterograde axonal transport. This is an unexpected and intriguing discovery on intracellular transport, and shed new light on the pathogenesis of PD.

关键词： Alpha-synuclein cytoplasmic dynein axonal transport Parkinson’s disease

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